Tag Archives: in silico

Phyllanthus tenellus and Kaempferia parviflora compounds inhibit SARS-CoV-2

J. Pharm. Pharmacogn. Res., vol. 10, no. 6, pp. 1103-1116, November-December 2022.

DOI: https://doi.org/10.56499/jppres22.1485_10.6.1103

Original Article

Phyllanthus tenellus Roxb. and Kaempferia parviflora Wall. ex Baker compounds as inhibitors of SARS-CoV-2 main protease and RNA-dependent RNA polymerase: A molecular docking study

[Compuestos de Phyllanthus tenellus Roxb. y Kaempferia parviflora Wall. ex Baker como inhibidores de la proteasa principal del SARS-CoV-2 y de la ARN polimerasa dependiente de ARN: Un estudio de acoplamiento molecular]

Suhaina Supian*, Muhamad Aizuddin Ahmad, Lina Rozano, Machap Chandradevan, Zuraida Ab Rahman

Biotechnology and Nanotechnology Research Centre, Malaysian Agricultural Research and Development Institute (MARDI), Serdang 43400, Selangor, Malaysia.

*E-mail: suhaina@mardi.gov.my

Abstract

Context: The outbreak of a novel coronavirus, SARS-CoV-2 has caused an unprecedented COVID-19 pandemic. To put an end to this pandemic, effective antivirals should be identified or developed for COVID-19 treatment. However, specific and effective antivirals or inhibitors against SARS-CoV-2 are still lacking.

Aims: To evaluate bioactive compounds from Phyllanthus tenellus and Kaempferia parviflora as inhibitorsagainst two essential SARS-CoV-2 proteins, main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), through molecular docking studies and to predict the drug-likeness properties of the compounds.

Methods: The inhibition potential and interaction of P. tenellus and K. parviflora compounds against Mpro and RdRp were assessed through molecular docking. The drug-likeness properties of the compounds were predicted using SwissADME and AdmetSAR tools.

Results: Rutin and ellagic acid glucoside from P. tenellus and 4-hydroxy-6-methoxyflavone and 5-hydroxy-3,7,4’-trimethoxyflavone from K. parviflora exhibited the highest binding conformations to Mpro by interacting with its substrate binding site that was predicted to halt the Mpro activity. As for RdRp, ellagitannin and rutin from P. tenellus and peonidin and 5,3’-dihydroxy-3,7,4’-trimethoxyflavone from K. parviflora were the best-docked compounds that bound to the RdRp catalytic domain (Asp760 and Asp761) and NTP-entry channel that were anticipated to stop RNA polymerization. However, in the context of drug developability, 4-hydroxy-6-methoxyflavone, 5-hydroxy-3,7,4’-trimethoxyflavone, peonidin and 5,3’-dihydroxy-3,7,4’-trimethoxyflavone from K. parviflora were highly potential to be oral active drugs compared to rutin, ellagic acid glucoside and ellagitannin from P. tenellus.

Conclusions: P. tenellus and K. parviflora compounds, particularly the aforementioned compounds, were suggested as potential inhibitors of SARS-CoV-2 Mpro and RdRp.

Keywords: antiviral; compounds; COVID-19; in silico; Kaempferia parviflora; Phyllanthus tenellus.

jppres_pdf_free

Resumen

Contexto: El brote de un nuevo coronavirus, el SARS-CoV-2, ha provocado una pandemia de COVID-19 sin precedentes. Para poner fin a esta pandemia, es necesario identificar o desarrollar antivirales eficaces para el tratamiento del COVID-19. Sin embargo, aún se carece de antivirales o inhibidores específicos y eficaces contra el SARS-CoV-2.

Objetivos: Evaluar compuestos bioactivos de Phyllanthus tenellus y Kaempferia parviflora como inhibidores contra dos proteínas esenciales del SARS-CoV-2, la proteasa principal (Mpro) y la ARN polimerasa dependiente del ARN (RdRp), mediante estudios de acoplamiento molecular y predecir las propiedades de similitud con los fármacos de los compuestos.

Métodos: El potencial de inhibición y la interacción de los compuestos de P. tenellus y K. parviflora contra la Mpro y la RdRp fueron evaluados mediante docking molecular. Las propiedades de semejanza de los compuestos se predijeron mediante las herramientas SwissADME y AdmetSAR.

Resultados: La rutina y el glucósido del ácido elágico de P. tenellus y la 4-hidroxi-6-metoxiflavona y la 5-hidroxi-3,7,4′-trimetoxiflavona de K. parviflora mostraron las conformaciones de unión más altas a Mpro al interactuar con su sitio de unión al sustrato que se predijo para detener la actividad de Mpro. En cuanto a la RdRp, la elagitanina y la rutina de P. tenellus y la peonidina y la 5,3′-dihidroxi-3,7,4′-trimetoxiflavona de K. parviflora fueron los compuestos mejor acoplados que se unieron al dominio catalítico de la RdRp (Asp760 y Asp761) y al canal de entrada NTP que se anticipó que detendría la polimerización del ARN. Sin embargo, en el contexto del desarrollo de fármacos, la 4-hidroxi-6-metoxiflavona, la 5-hidroxi-3,7,4′-trimetoxiflavona, la peonidina y la 5,3′-dihidroxi-3,7,4′-trimetoxiflavona de K. parviflora tendrían un gran potencial para ser fármacos activos por vía oral en comparación con la rutina, el glucósido de ácido elágico y la elagitanina de P. tenellus.

Conclusiones: Los compuestos de P. tenellus y K. parviflora, en particular los mencionados, fueron sugeridos como potenciales inhibidores de Mpro y RdRp del SARS-CoV-2.

Palabras Clave: antiviral; compuestos; COVID-19; in silico; Kaempferia parviflora; Phyllanthus tenellus.

jppres_pdf_free
Citation Format: Supian S, Ahmad MA, Rozano L, Chandradevan M, Ab Rahman Z (2022) Phyllanthus tenellus Roxb. and Kaempferia parviflora Wall. ex Baker compounds as inhibitors of SARS-CoV-2 main protease and RNA-dependent RNA polymerase: A molecular docking study. J Pharm Pharmacogn Res 10(6): 1103–1116. https://doi.org/10.56499/jppres22.1485_10.6.1103
References

Aftab SO, Ghouri MZ, Masood MU, Haider Z, Khan Z, Ahmad A, Munawar N (2020)Analysis of SARS-CoV-2 RNA-dependent RNA polymerase as a potential therapeutic drug target using a computational approach. J Transl Med 18(1): 275. https://doi.org/10.1186/s12967-020-02439-0

Amin ML (2013) P-glycoprotein inhibition for optimal drug delivery. Drug Target Insights 7: 27–34. https://doi.org/10.33393/dti.2013.1349

Babar M, Najam‑Us‑Sahar SZ, Ashraf M, Kazi AG (2013) Antiviral drug therapy – Exploiting medicinal plants. J Antivir Antiretrovir 5: 28–36. https://doi.org/10.4172/2155-6113.1000215

Ben-Shabat S, Yarmolinsky L, Porat D, Dahan A (2020) Antiviral effect of phytochemicals from medicinal plants: Applications and drug delivery strategies. Drug Deliv Transl Res 10(2): 354–367. https://doi.org/10.1007/s13346-019-00691-6

Chen D, Li H, Li W, Feng S, Deng D (2018) Kaempferia parviflora and its methoxyflavones: Chemistry and biological activities. Evid Based Complement Alternat Med 2018: 4057456. https://doi.org/10.1155/2018/4057456

Cheng F, Li W, Zhou Y, Shen J, Wu Z, Liu G, Lee PW, Tang Y (2012) admetSAR: a comprehensive source and free tool for assessment of chemical ADMET properties. J Chem Inf Model 52(11): 3099–3105. https://doi.org/10.1021/ci300367a

Cheng PW, Ng LT, Chiang LC, Lin CC (2006) Antiviral effects of saikosaponins on human coronavirus 229E in vitro. Clin Exp Pharmacol Physiol 33(7): 612–616. https://doi.org/10.1111/j.1440-1681.2006.04415.x

Daina A, Zoete V (2016) A BOILED-Egg to predict gastrointestinal absorption and brain penetration of small molecules. ChemMedChem 11: 1117–1121. https://doi.org/10.1002/cmdc.201600182

Eweas AF, Alhossary AA, Abdel-Moneim AS (2021) Molecular docking reveals ivermectin and remdesivir as potential repurposed drugs against SARS-CoV-2. Front Microbiol 11: 592908. https://doi.org/10.3389/fmicb.2020.592908

Farouk F, Shamma R (2019) Chemical structure modifications and nano-technology applications for improving ADME-Tox properties, a review. Arch Pharm Chem Life Sci 352(2): e1800213. https://doi.org/10.1002/ardp.201800213

Jin Z, Wang H, Duan Y, Yang H (2020) The main protease and RNA-dependent RNA polymerase are two prime targets for SARS-CoV-2. Biochem Biophys Res Commun 538: 63–71. https://doi.org/10.1016/j.bbrc.2020.10.091

Gao Y, Yan L, Huang Y, Liu F, Zhao Y, Cao L, Wang T, Sun Q, Ming Z, Zhang L, Ge J, Zheng L, Zhang Y, Wang H, Zhu Y, Zhu C, Hu T, Hua T, Zhang B, Yang X, Li J, Yang H, Liu Z, Xu W, Guddat LW, Wang Q, Lou Z, Rao Z (2020) Structure of the RNA-dependent RNA polymerase from COVID-19 virus. Science 368: 779–782. https://doi.org/10.1126/science.abb7498

Gentile D, Patamia V, Scala A, Sciortino MT, Piperno A, Rescifina (2020) Putative inhibitors of SARS-CoV-2 main protease from a library of marine natural products: A virtual screening and molecular modeling study. Mar Drugs 18(4): 225. https://doi.org/10.3390/md18040225

Ghanimi R, Ouhammou A, El Atki Y, Cherkaoui M (2022) Molecular docking study of the main phytochemicals of some medicinal plants used against COVID-19 by the rural population of Al-Haouz region, Morocco. J Pharm Pharmacogn Res 10(2): 227–238. https://doi.org/10.56499/jppres21.1200_10.2.227

Goyal B, Goyal D (2020) Targeting the dimerization of the main protease of coronaviruses: A potential broad-spectrum therapeutic strategy. ACS Comb Sci 22(6): 297–305. https://doi.org/10.1021/acscombsci.0c00058

Kharisma VD, Aghata A, Ansori ANM, Widyananda MH, Rizky WC, Dings TGA, Derkho M, Lykasova I, Antonius Y, Rosadi I, Zainul R (2022) Herbal combination from Moringa oleifera Lam. and Curcuma longa L. as SARS-CoV-2 antiviral via dual inhibitor pathway: A viroinformatics approach. J Pharm Pharmacogn Res 10(1): 138–146. https://doi.org/10.56499/jppres21.1174_10.1.138

Lamb YN (2022) Nirmatrelvir plus ritonavir: first approval. Drugs 82:585–591. https://doi.org/10.1007/s40265-022-01692-5  

Long C, Romero ME, La Rocco D, Yu J (2021) Dissecting nucleotide selectivity in viral RNA polymerases. Comput Struct Biotechnol J 19: 3339–3348. https://doi.org/10.1016/j.csbj.2021.06.005

Martin R, Li J, Parvangada A, Perry J, Cihlar T, Mo H, Porter D, Svarovskaia E (2021) Genetic conservation of SARS-CoV-2 RNA replication complex in globally circulating isolates and recently emerged variants from humans and minks suggests minimal pre-existing resistance to remdesivir. Antiviral Res 188: 105033. https://doi.org/10.1016/j.antiviral.2021.105033

Mehrbod P, Hudy D, Shyntum D, Markowski J, Łos MJ, Ghavami S (2021) Quercetin as a natural therapeutic candidate for the treatment of influenza virus. Biomol 11(1): 10. https://doi.org/10.3390/biom11010010

Mohammad Zadeh N, Mashinchi Asl NS, Forouharnejad K, Ghadimi K, Parsa S, Mohammadi S, Omidi A (2021) Mechanism and adverse effects of COVID-19 drugs: a basic review. Int J Physiol Pathophysiol Pharmacol 13(4): 102–109.

Mohd Jusoh NH, Subki A, Yeap SK, Yap KC, Jaganath IB (2019) Pressurized hot water extraction of hydrosable tannins from Phyllanthus tenellus Roxb. BMC Chem 13(1): 134. https://doi.org/10.1186/s13065-019-0653-0

Nutan MM, Goel T, Das T, Malik S, Suri S, Rawat AKS, Srivastava SK, Tuli R, Malhotra S, Gupta SK (2013) Ellagic acid & gallic acid from Lagerstroemia speciosa L. inhibit HIV-1 infection through inhibition of HIV-1 protease & reverse transcriptase activity. Indian J Med Res 137: 540–548.

Oh C, Price J, Brindley MA, Widrlechner MP, Qu L, McCoy JA, Murphy P, Hauck C, Maury W (2011) Inhibition of HIV-1 infection by aqueous extracts of Prunella vulgaris L. Virol J 8: 188. https://doi.org/10.1186/1743-422X-8-188

Ortega JT, Suárez AI, Serrano ML, Baptista J, Pujol FH, Rangel HR (2017) The role of the glycosyl moiety of myricetin derivatives in anti-HIV-1 activity in vitro. AIDS Res Ther 14(1): 57. https://doi.org/10.1186/s12981-017-0183-6

Pitts J, Li J, Perry JK, Du Pont V, Riola N, Rodriguez L, Lu X, Kurhade C, Xie X, Camus G, Manhas S, Martin R, Shi PY, Cihlar T, Porter DP, Mo H, Maiorova E, Bilello JP (2022) Remdesivir and GS-441524 retain antiviral activity against delta, omicron, and other emergent SARS-CoV-2 variants. Antimicrob Agents Chemother 66(6): e0022222. https://doi.org/10.1128/aac.00222-22

Ritchie TJ, Macdonald SJ (2009) The impact of aromatic ring count on compound developability–are too many aromatic rings a liability in drug design? Drug Discovery Today 14(21/22): 1011–1020. https://doi.org/10.1016/j.drudis.2009.07.014

Shivanika C, Deepak Kumar S, Venkataraghavan R, Pawan T, Sumitha A, Brindha Devi P (2020) Molecular docking, validation, dynamics simulations, and pharmacokinetic prediction of natural compounds against the SARS-CoV-2 main-protease. J Biomol Struct Dyn 40(2): 585–611. https://doi.org/10.1080/07391102.2020.1815584

Silva T, Veras Filho J, Lúcia CDAE, Antonia DSI, Albuquerque U, Cavalcante de Araújo E (2012) Acute toxicity study of stone-breaker (Phyllanthus tenellus Roxb.). Rev Cienc Farm 33: 205–210.

Sookkongwaree K, Geitmann M, Roengsumran S, Petsom A, Danielson UH (2006) Inhibition of viral proteases by Zingiberaceae extracts and flavones isolated from Kaempferia parviflora. Pharmazie 61(8): 717–721.

Sornpet B, Potha T, Tragoolpua Y, Pringproa K (2017) Antiviral activity of five Asian medicinal pant crude extracts against highly pathogenic H5N1 avian influenza virus. Asian Pac J Trop Med 10(9): 871–876. https://doi.org/10.1016/j.apjtm.2017.08.010

Tai W, He L, Zhang X, Pu J, Voronin D, Jiang S, Zhou Y, Du L (2020) Characterization of the receptor-binding domain (RBD) of 2019 novel coronavirus: Implication for development of RBD protein as a viral attachment inhibitor and vaccine. Cell Mol Immunol 17(6): 613–620. https://doi.org/10.1038/s41423-020-0400-4

Tan WC, Jaganath IB, Manikam R, Sekaran SD (2013) Evaluation of antiviral activities of four local Malaysian Phyllanthus species against herpes simplex viruses and possible antiviral target. Int J Med Sci 10(13): 1817–1829. https://doi.org/10.7150/ijms.6902

Tao J, Hu Q, Yang J, Li R, Li X, Lu C, Chen C, Wang L, Shattock R, Ben K (2007) In vitro anti-HIV and -HSV activity and safety of sodium rutin sulfate as a microbicide candidate. Antiviral Res75(3): 227–233. https://doi.org/10.1016/j.antiviral.2007.03.008

te Velthuis AJ, Arnold JJ, Cameron CE, van den Worm SH, Snijder EJ (2010) The RNA polymerase activity of SARS-coronavirus nsp12 is primer dependent. Nucleic Acids Res 38(1): 203–214. https://doi.org/10.1093/nar/gkp904

te Velthuis AJ, van den Worm SH, Snijder EJ (2012) The SARS-coronavirus nsp7+nsp8 complex is a unique multimeric RNA polymerase capable of both de novo initiation and primer extension. Nucleic Acids Res 40(4): 1737–1747. https://doi.org/10.1093/nar/gkr893

Vangeel L, Chiu W, De Jonghe S, Maes P, Slechten B, Raymenants J, André E, Leyssen P, Neyts J, Jochmans D (2022) Remdesivir, Molnupiravir and Nirmatrelvir remain active against SARS-CoV-2 Omicron and other variants of concern. Antiviral Res 198: 105252. https://doi.org/10.1016/j.antiviral.2022.105252

Xue B, Blocquel D, Habchi J, Uversky AV, Kurgan L, Uversky VN, Longhi S (2014) Structural disorder in viral proteins. Chem Rev 114(13): 6880–6911. https://doi.org/10.1021/cr4005692

Yenjai C, Prasanphen K, Daodee S, Wongpanich V, Kittakoop P (2004) Bioactive flavonoids from Kaempferia parviflora. Fitoterapia 75(1): 89–92. https://doi.org/10.1016/j.fitote.2003.08.017

Zhang L, Lin D, Sun X, Curth U, Drosten C, Sauerhering L, Becker S, Rox K, Hilgenfeld R (2020) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors. Science 368: 409–412. https://doi.org/10.1126/science.abb3405

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL (2020) Addendum: A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 588(7836): E6. https://doi.org/10.1038/s41586-020-2951-z

Zhu Z, Lian X, Su X, Wu W, Marraro GA, Zeng Y (2020) From SARS and MERS to COVID-19: A brief summary and comparison of severe acute respiratory infections caused by three highly pathogenic human coronaviruses. Respir Res 21(1): 224. https://doi.org/10.1186/s12931-020-01479-w

© 2022 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

Caesalpinia sappan nanoemulgel as an antiaging

J. Pharm. Pharmacogn. Res., vol. 10, no. 5, pp. 922-937, September-October 2022.

DOI: https://doi.org/10.56499/jppres22.1456_10.5.922

Original Article

Secang wood (Caesalpinia sappan L.) nanoemulgel activity as antiaging through suppressing the MMP-1 expression and the collagen degradation

[Actividad del nanoemulgel de secang wood (Caesalpinia sappan L.) como antienvejecimiento mediante la supresión de la expresión de MMP-1 y la degradación del colágeno]

Ni Putu Linda Laksmiani1*, Ni Putu Eka Leliqia1, Ni Luh Putu Vidya Paramita1, I Gusti Kamasan Nyoman Arijana2, Ni Putu Ayu Dewi Wijayanti1, Putu Ivan Adiwibawa1, I Made Harimbawa Putra1, I Putu Ari Anggara Catur Pratama1

1Department of Pharmacy, Mathematics and Natural Science Faculty, Udayana University, Indonesia.

2Biochemistry Department, Faculty of Medicine, Udayana University, Indonesia.

*E-mail: laksmini@unud.ac.id

Abstract

Context: Aging is closely related to reactive oxygen species (ROS). ROS increases the collagenase enzyme (MMP-1) levels and collagen degradation that causes skin wrinkling. Secang wood (Caesalpinia sappan L.) containing brazilin and brazilein has been shown to have photoprotective and antioxidant properties.

Aims: To evaluate the activity of C. sappan nanoemulgel as antiaging agent against the target protein, matrix metalloproteinases (MMPs), especially MMP-1, MMP-3, and MMP-9 by in silico assay and using in vivo assay through MMP-1 and collagen expression parameter.

Methods: C. sappan nanoemulgel was made by mixing the gel base with C. sappan nanoemulsion from heartwood extract. The C. sappan nanoemulsion was formulated using the Self Nanoemulsifying Drug Delivery System method. In vivo testing was conducted with a post-test-only control group design and used male Wistar rats. MMP-1 expression was examined using immunohistochemical techniques, and the amount of dermal collagen was observed with Picro Sirius Red staining. In silico assay using a computational method with Autodock 4.2 program.

Results: C. sappan nanoemulgel concentrations of 0.0625, 0.125, and 0.25% obstruct the expression of MMP-1 and collagen degradation. The bond energy value to MMP-1, MMP-3, and MMP-9 were -8.04, -10.40, and -8.70 kcal/mol (for brazilin);  -8.82; -10.99, and -8.51 kcal/mol (for brazilein).

Conclusions: Nanoemulgel containing C. sappan nanoemulsion has a potential activity as an antiaging agent by repressing MMP-1 expression and dermal collagen degradation. C. sappan nanoemulgel 0.25% showed the best result as antiaging. Brazilin and brazilein from C. sappan inhibit the MMP-1, MMP-3, and MMP-9 by in silico assay.

Keywords: antiaging; collagen; in silico; in vivo; MMP-1.

Resumen

Contexto: El envejecimiento está estrechamente relacionado con las especies reactivas de oxígeno (ROS). ROS aumenta los niveles de la enzima colagenasa (MMP-1) y la degradación del colágeno que causa las arrugas en la piel. Se ha demostrado que la madera de secang (Caesalpinia sappan L.) que contiene brasilina y brasilina tiene propiedades fotoprotectoras y antioxidantes.

Objetivos: Evaluar la actividad de C. sappan nanoemulgel como agente antienvejecimiento contra la proteína diana, las metaloproteinasas de matriz (MMP), especialmente MMP-1, MMP-3 y MMP-9 mediante ensayo in silico y usando ensayo in vivo a través de MMP-1 y parámetro de expresión de colágeno.

Métodos: El nanoemulgel de C. sappan se elaboró mezclando la base del gel con la nanoemulsión del extracto de duramen de C. sappan. Esta se formuló utilizando el método del sistema de liberación de fármaco autonanoemulsionante. Las pruebas in vivo se realizaron con un diseño de grupo de control solo posterior a la prueba y se utilizaron ratas Wistar macho. La expresión de MMP-1 se examinó mediante técnicas inmunohistoquímicas y la cantidad de colágeno dérmico se observó con tinción con Picro Sirius Red. El ensayo in silico utilizó un método computacional con el programa Autodock 4.2.

Resultados: Las concentraciones de C. sappan nanoemulgel de 0,0625; 0,125 y 0,25% inhiben la expresión de MMP-1 y la degradación del colágeno. El valor de la energía de enlace para MMP-1, MMP-3 y MMP-9 fue -8,04; -10,40 y -8,70 kcal/mol (para brasilina); -8,82; -10,99 y -8,51 kcal/mol (para brazilein).

Conclusiones: El nanoemulgel que contiene nanoemulsión de C. sappan tiene una actividad potencial como agente antienvejecimiento al reprimir la expresión de MMP-1 y la degradación del colágeno dérmico. C. sappan nanoemulgel 0,25% mostró el mejor resultado como antienvejecimiento. Brazilin y brazilein de C. sappan inhiben MMP-1, MMP-3 y MMP-9 mediante ensayo in silico.

Palabras Clave: antienvejecimiento; colágeno; in silicio; in vivo; MMP-1.

Citation Format: Laksmiani NPLL, Leliqia NPE, Paramita NLPV, Arijana IGKN, Wijayanti NPAD, Adiwibawa PI, Putra IMH, Pratama IPAAC (2022) Secang wood (Caesalpinia sappan L.) nanoemulgel activity as antiaging through suppressing the MMP-1 expression and the collagen degradation. J Pharm Pharmacogn Res 10(5): 922–937. https://doi.org/10.56499/jppres22.1456_10.5.922
References

Al-Niaimi F, Chiang NYZ (2017) Topical vitamin C and the skin: Mechanism of action and cllinical applications. JClin Aesthet Dermatol 10(7): 14–17.

Bayerl C (2016) Skin aging and evidence-based topical strategies. Hautarzt 67(2): 140–147.

Bernardi DS, Pereira TA, Maciel NR, Bortoloto J, Viera GS, Oliveira GC, Rocha PA (2011) Formation and stability of oil-in-water nanoemulsions containing rice bran oil: in vitro and in vivo assessments. J Biotechnol 9: 44.

Chellapa P, Mohamed AT, Keleb EI, Elmahgoubi A, Eid AM, Issa YS, Elmarzugi NA (2015) Nanoemulsion and nanoemulgel as a topical formulation. IOSR J Pharm 5(10): 43–47.

Costa JA, Lucas EF, Queirús YGC, Mansur CRE (2012) Evaluation of nanoemulions in the cleaning of polymeric resins. Colloids Surf Physicochem Eng Asp 415: 112–118.

Ferreira LG, Santos RND, Oliva G, Andricapulo AD (2015) Molecular docking and structure-based drug design strategies. Molecules20: 13384–13421.

Firas AN, Nicole YZC (2017) Topical vitamin C and the skin: Mechanism of action and clinical applications. J Clin Aesthet Dermatol 10(7): 14–17.

Forgiarini A, Esquena J, Gonzales C, Solans C (2001) Formation of nano-emulsions by low energy emulsification methods at constant temperature. Langmuir 17 (Suppl 7): 2076–2083.

Garg A, Aggarwal SG, Sigla AK (2002) Spreading of Semisolid Formulation. USA: Pharmaceutical Technology.

Gutierrez JM, Gonzales C, Maestro A, Sole I, Pey CM, Nolla J (2008) Nano-emulsions: New applications and optimization of their preparation. Curr Opin Colloid Interface Sci 13(4): 245–251.

Huey R, Morris GM, Forli S (2012) Using AutoDock 4 and AutoDock Vina with AutoDockTools: A Tutorial, The Scripps Research Institute, California.

Hwang YP, Kim HG, Choi JH, Han EH, Kwon KI, Lee YC (2011) Saponins from the roots of Platycodon grandiflorum suppress ultraviolet A-induced matrix metalloproteinase-1 expression via MAPKs and NF-kB/AP-1-dependent signaling in HaCaT Cells. Food Chem Toxicol 49: 3374–3382.

Jain AN, Nicholls A (2008) Recomendations for evaluation of computational method, J Comput Aided Mol Des 22: 133–139.

Kale SN, Deore SL (2017) Emulsion micro emulsion and nano emulsion: A review. Sys Rev Pharm 8: 39–47.

Karim AA, Azlan A, Ismail A, Hashim P, Gani S, Zainudin BH, Abdullah NA (2014) Phenolic composition, antioxidant, anti-wrinkles and tyrosinase inhibitory activities of cocoa pod extract. BMC Complement Altern Merd 14: 381.

Kitchen DB, Decornez H, Furr JR, Bajorath J (2004) Docking and scoring in virtual screening for drug discovery: methods and applications. Nat Rev Drug Discov 3: 935–949.

Kong R, Cui Y, Fisher GJ, Wang X, Chen Y, Schneider LM (2015) A comparative study of the effects of retinol and retinoic acid on histological, molecular, and clinical properties of human skin. J Cosmet Dermatol 15: 49–57.

Laksmiani NPL, Leliqia NPE, Armita PMN, Arijana NIGK, Saputra AABY, Prananingtyas KI (2020) In-silico and in-vitro studies of antioxidant and sun protection activities of sappan wood (Caesalpinia sappan L.). Trop J Nat Prod Res 4(12): 1072–1080.

Laksmiani NPL, Nugraha IPW (2019) Depigmentation activity of secang (Caesalpinia sappan L.) extract through tyrosinase, tyrosinase related protein-1 and dopachrome tautomerase inhibition. Biomed Pharmacol J 12(2): 709–808.

Lin TY, Wu PY, Hou CW, Chien TY, Chang QX, Wen KC, Lin CY, Chiang HM (2019) Protective effects of sesamin against UVB-induced skin inflammation and photodamage in vitro and in vivo. Biomolecules 9(9): 479–502.

Makadia HA, Bhatt AY, Parmar RB, Paun JS, Tank HM (2013) Self-nano emulsifying drug delivery system (SNEDDS): Future aspect.Asian J Pharm Res 3: 21-27.

Morris GM, Goodsell DS, Pique ME, Lindstrom WL, Huey R, Forli S, Hart WE, Halliday S, Belew R, Olson AJ (2012) Autodock Version 4.2: Automated Docking of Flexible Ligands to Rigid Receptors, USA: The Scripps Research Institute.

Mukesh B, Rakesh K (2011) Molecular docking: A review. Int J Ayurveda Res 2: 1746–1751.

Mukherjee PK, Maity N, Nema NK, Sarkar BK (2011) Bioactive compounds from natural resources against skin aging. Phytomedicine 19(1): 64–73.

Mukubwa GK, Nkanga CI, Buya AB, Mbinze JK, Krause RWM, Memvanga PB (2020) Self-nanoemulsifying drug delivery systems (SNEDDS) for oral delivery of Garcinia kola seeds ethanolic extract: formulation and in vivo antimalarial activity. J Pharm Pharmacogn Res 8(3): 177–190.

Mulyani S, Harsodjuwono BA, Wiraguna AAGP (2017) The potential of tumeric and tamarind leaves extract (Curcuma domestica Val – Tamarindus indica L) as anti-collagenase cream. J Chem Pharm Res 9(12): 111–118.

Naidoo K, Birch-Machin MA (2017) Oxidative stress and ageing: the influence of enviromental pollution, sunlight and diet on skin. Cosmetics 4: 4.

Niu Y, Wang S, Li C, Wang J, Liu Z, Kang W (2020) Effective compounds from Caesalpinia sappan L. on the tyrosinase in vitro and in vivo. Nat Prod Commun 15(4): 1–8.

Nurman S, Yulia R, Irmayanti, Noor E, Sunarti TC (2019) The optimization of gel preparations using the active compounds of Arabica coffee ground nanoparticles. Sci Phar 87: 32

Pientaweeratch S, Panapisal V, Tansirikongkol A (2016) Antioxidant, anti-collagenase and anti-elastase activities of Phyllantus emblica, Manilkara zapota, and silymarin: An in vitro comparative study for antiaging applications. Pharm Biol 54(9): 1865–1872.

Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M (2016) Role of matrix metalloproteinases in photoaging and photocarcinogenesis. Int J Mol Sci 17(6): 868.

Pouillot A, Polla B (2011) Natural antioxidants and their effects on the skin. Formul. Packag Mark Nat Cosmet Prod Ed Dayan N Kromidas L.

Sokolov YV (2014) Nanoemulsion formulation by low-energy methods: A Review.News Pharm 3: 16–18.

Tadros TF (2005)Applied Surfactans: Surfactans, In Nanoemulsions, Weinheim: Wiley-VCH Verlag.

Varma SR, Mishra A, Vijayakumar M, Paramesh R (2017) Anti-skin aging phytochemicals in cosmetics: An appraisal. Househ Pers Care Today 12(2): 20–23.

Wang M, Lu W, Ge X, Lu Y, Jia X, Li H, Liu Q (2022) Study on the efficacy of vitamin C lotion on skin: Permeable and antiaging. J Cosmet Dermatol Sci Appl 12(1): 67–82.

Wongrattanakamon P, Nimmanpipug P, Sirithunyalug B, Chaiyana W, Jiranusornkul S (2018) Molecular modeling of non-covalent binding of Ligustrum lucidum secoiridoid glucosides to AP-1/matrix metalloproteinase pathway components. J Bioenerg Biomembr50(4): 315–327.

Xiao X, Huang M, Fan C, Zuo F (2018) Research on the senescence of human skin fibroblasts induced by ultraviolet B and its mechanism. Biomed Res 29(2): 313–316.

Zhang S, Duan E (2018) Fighting against skin aging: the way from bench to bedside. Cell Transplant 27: 729–738.

© 2022 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

Molecular docking of polyether ether ketone and nano-hydroxyapatite in orthodontics

J. Pharm. Pharmacogn. Res., vol. 10, no. 4, pp. 676-686, July-August 2022.

DOI: https://doi.org/10.56499/jppres22.1371_10.4.676

Original Article

Molecular docking of polyether ether ketone and nano-hydroxyapatite as biomaterial candidates for orthodontic mini-implant fabrication

[Acoplamiento molecular de poliéter éter cetona y nano-hidroxiapatita como biomateriales candidatos para la fabricación de mini-implantes de ortodoncia]

I Gusti Aju Wahju Ardani1,2, Alexander Patera Nugraha1,2,3*, Monika Nilam Suryani1, Ryan Hafidz Putra Pamungkas1, Devani Githa Vitamamy1, Rizky Alif Susanto1, Riyanarto Sarno4, Aziz Fajar4, Viol Dhea Kharisma5, Albertus Putera Nugraha6, Tengku Natasha Eleena binti Tengku Ahmad Noor7,8

1Orthodontics Department, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

2Dental Implant Research Group, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

3Graduate Student of Dental Health Science, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

4Department of Informatics, Institut Teknologi Sepuluh Nopember, Surabaya, Indonesia.

5Department of Biology, Faculty of Mathematics and Natural Science, Universitas Brawijaya, Malang, Indonesia.

6Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.

7Membership of Faculty of Dental Surgery, Royal College of Surgeons, Edinburgh University, United Kingdom.

8Malaysian Armed Forces Dental Officer, 609 Armed Forces Dental Clinic, Kem Semenggo, Kuching, Sarawak, Malaysia.

*E-mail: alexander.patera.nugraha@fkg.unair.ac.id

Abstract

Context: Modified polyether ether ketone (PEEK) by adding nano-hydroxyapatite (HA) material on its fixture for mini-implant fabrication may increase resistance force through osseointegration.

Aims: To analyze the binding molecular docking of PEEK incorporated with HA as a biomaterial candidate for orthodontic mini-implant fabrication through a bioinformatic approach, an in silico study.

Methods: 3D ligand structure consisting of HA, PEEK and target proteins consisting of osteopontin, osteocalcin, osteonectin, bone morphogenetic protein 4 (BMP4), bone morphogenetic protein 2 (BMP2), bone morphogenetic protein 7 (BMP7), alkaline phosphatase (ALP),  runt-related transcription factor 2 (RUNX2), Insulin growth factor-1 (IGF-1), osterix, tartrate-resistant acid phosphatase (TRAP), collagen alpha-1 (COL1A1) obtained from RCSB-PDB. It was analyzed the binding affinity of a single HA, PEEK, and HA + PEEK complex to twelve target proteins related to osseointegration. The types of chemical interactions produced by the ligands in the target protein domain consisted of Van der Waals, hydrogen, hydrophobic, pi, and alkyl.

Results: The blind docking simulation succeeded in identifying the most negative binding affinity; it was found in the HA + PEEK molecular complex compared to HA and PEEK in the single condition. The type of chemical interaction formed consisted of hydrogen, van der Waals, pi, and alkyl. HA+PEEK showed the most negative binding affinity with ALP and IGF-1, as much as -8.7 binding affinity.

Conclusions: The molecular docking of PEEK with HA exhibited a prominent binding affinity with osteogenic markers like ALP and IGF-1 in silico, allowing it to have a higher potential than nano-HA or PEEK as a single biomaterial for osseointegration as the fabrication of mini-implants that may support orthodontic treatment.

Keywords: dentistry; good health and well-being; in silico; medicine; temporary anchorage device.

This image has an empty alt attribute; its file name is jppres_pdf_free.png

Resumen

Contexto: La poliéter éter cetona modificada (PEEK) puede aumentar la fuerza de resistencia a través de la osteointegración mediante la adición de material de nanohidroxiapatita (HA) para la fabricación de mini-implantes.

Objetivos: Analizar el acoplamiento molecular de PEEK incorporado con HA como candidato a biomaterial para la fabricación de miniimplantes de ortodoncia a través de un enfoque bioinformático, un estudio in silico.

Métodos: Estructura de ligando 3D que consiste en HA, PEEK y proteínas diana como osteopontina, osteocalcina, osteonectina, proteína morfogenética ósea 4 (BMP4), proteína morfogenética ósea 2 (BMP2), proteína morfogenética ósea 7 (BMP7), fosfatasa alcalina (ALP) , factor de transcripción relacionado con runt 2 (RUNX2), factor de crecimiento de insulina-1 (IGF-1), osterix, fosfatasa ácida tartrato resistente (TRAP), colágeno alfa-1 (COL1A1) obtenido de RCSB-PDB. Fue analizada la afinidad de unión del complejo único HA, PEEK y HA + PEEK a doce proteínas diana relacionadas con la osteointegración. Los tipos de interacciones químicas producidas por los ligandos en el dominio de la proteína objetivo consistieron en Van der Waals, hidrógeno, hidrofóbico, pi y alquilo.

Resultados: La simulación a ciegas de acoplamiento logró identificar la afinidad de unión más negativa. Esta se encontró en el complejo molecular HA + PEEK en comparación con HA y PEEK de forma individual. El tipo de interacción química formada consistió en hidrógeno, van der Waals, pi y alquilo. HA+PEEK mostró la afinidad de unión más negativa con ALP e IGF-1, con una afinidad de unión de -8,7.

Conclusiones: El acoplamiento molecular de PEEK con HA exhibió una afinidad de unión prominente con marcadores osteogénicos como ALP e IGF-1 in silico, lo que le permite tener un mayor potencial que HA o PEEK como biomaterial único para la osteointegración como la fabricación de mini-implantes que puedan soportar el tratamiento de ortodoncia.

Palabras Clave: buena salud y bienestar; dispositivo de anclaje temporal; in silico; odontología; medicina.

This image has an empty alt attribute; its file name is jppres_pdf_free.png

Citation Format: Ardani IGAW, Nugraha AP, Suryani NM, Pamungkas RH, Vitamamy DG, Susanto RA, Sarno R, Fajar A, Kharisma VD, Nugraha AP, Noor TNEBTA (2022) Molecular docking of polyether ether ketone and nano-hydroxyapatite as biomaterial candidates for orthodontic mini-implant fabrication. J Pharm Pharmacogn Res 10(4): 676–686. https://doi.org/10.56499/jppres22.1371_10.4.676
References

Albrektsson T, Johansson C (2001) Osteoinduction, osteoconduction and osseointegration. Eur Spine J 10: S96–S101.

Alqahtani AR, Gufran K, Silva F, Rocha MG, Chang J (2021) A clinical case report of a potential acute allergic reaction with titanium dental implant. Case Rep Dent 2021: 5592934.

Antolis M, Anggani HS, Marshadianti D, Ayu D (2021) Mini implant orthodontic as an anchorage in skeletal class II malocclusion treatment with severe dental protrusion [Indonesian]. J Ked Gi Unpad 33(1):71–78.

Ardani IG, Rahmawati D, Narmada IB, Nugraha AP, Taftazani H, Kusumawardani MK (2020) Surface Electromyography unveil the relationship between masticatory muscle tone and maloclusion class I & II in Javanese ethnic patient. J Int Dent Med Res 13(4): 1447–1454.

Barkarmo S, Wennerberg A, Hoffman M, Kjellin P, Breding K, Handa P, Stenport V (2013) Nano-hydroxyapatite-coated PEEK implants: A pilot study in rabbit bone. J Biomed Mater Res Part A 101A(2): 465–471.

Cheng Z, Guo C, Dong W, He FM, Zhao SF, Yang GL (2012) Effect of thin nano-hydroxyapatite coating on implant osseointegration in ovariectomized rats. Oral Surg Oral Med Oral Pathol Oral Radiol 113(3): e48-e53.

Choi JW, Shin S, Lee CY, Lee J, Seo HH, Lim S, Lee S, Kim IK, Lee HB, Kim SW, Hwang KC (2017) Rapid induction of osteogenic markers in mesenchymal stem cells by adipose-derived stromal vascular fraction cells. Cell Physiol Biochem 44(1): 53–65.

de Oliveira PGFP, de Melo Soares MS, Silveira E Souza AMM (2021) Influence of nano-hydroxyapatite coating implants on gene expression of osteogenic markers and micro-CT parameters. An in vivo study in diabetic rats. J Biomed Mater Res A 109(5): 682–694.

Elias CN, Oliveira Ruellas AC, Fernandes DJ (2012) Orthodontic implants: Concepts for the orthodontic practitioner. Int J Dent 2012: 549761.

Geng YM, Ren DN, Li SY, Li ZY, Shen XQ, Yuan YY (2020) Hydroxyapatite-incorporation improves bone formation on endosseous PEEK implant in canine tibia. J Appl Biomater Funct Mater 18: 2280800020975172.

Gromolak S, Krawczenko A, Antończyk A, Buczak K, Kiełbowicz Z, Klimczak A (2020) Biological characteristics and osteogenic differentiation of ovine bone marrow derived mesenchymal stem cells stimulated with FGF-2 and BMP-2. Int J Mol Sci 21(24): 9726.

Guo T, Kang W, Xiao D, Duan R, Zhi W, Weng J (2013) Molecular docking characterization of a four-domain segment of human fibronectin encompassing the RGD loop with hydroxyapatite. Molecules 19(1): 149–158.

Gupitasari A, Putri LS (2018) The prevalence of bad habits as the etiology of angle’s class I malocclusion in orthodontic clinic dental hospital Jember in 2015-2016 [Indonesian]. Pus Kes 6(2): 365–370.

Hayman AR (2008) Tartrate-resistant acid phosphatase (TRAP) and the osteoclast/immune cell dichotomy. Autoimmunity 41(3):218-223.

Henry JP, Bordoni B (2021) Histology, Osteoblasts. In: StatPearls. Treasure Island (FL): StatPearls Publishing; Update May 10, 2021.

Herwanda H, Arifin R, Lindawati L (2016) Knowledge of adolescents age 15-17 at SMAN 4 Banda Aceh City on the side effects of using fixed orthodontic appliances  [Indonesian]. J Syiah Kuala Dent Soc 1(1): 79–84.

Jubhari EH, Dammar I, Launardo V, Goan Y (2020) Implant coating materials to increase osseointegration of dental implant: A systematic review. Sys Rev Pharm 11(12): 35–41.

Kazimierczak P, Przekora A (2020) Osteoconductive and osteoinductive surface modifications of biomaterials for bone regeneration: A concise review. Coatings 10(10): 971.

Kharisma VD, Ansori AN, Nugraha AP (2020) Computational study of ginger (Zingiber officinale) as E6 Inhibitor in human papillomavirus type 16 (HPV-16) infection. Biochem Cell Arch 20: 3155–3159.

Khotib J, Lasandara CSC, Samirah S, Budiatin AS (2019) Acceleration of bone fracture healing through the use of natural bovine hydroxyapatite implant on bone defect animal model. Fol Med Indones 55(33): 176-187.

Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, Han L, He J, He S, Shoemaker BA, Wang J (2016) PubChem Substance and Compound databases. Nucleic Acids Res 44(D1): D1202–D1213.

Levingstone TJ, Ardhaoui M, Benyounis K, Looney L, Stokes JT (2015) Plasma sprayed hydroxyapatite coatings: Understanding process relationships using design of experiment analysis. Surf Coat Technol 283: 29–36.

Loblobly M, Anindita PS, Leman MA (2015) Gambaran Maloklusi Berdasarkan Indeks Handicapping Malocclusion Assessment Record (HMAR) Pada Siswa SMAN 9 Manado [Indonesian]. e-GiGi 3(2): 625­–633.

Luqman A, Kharisma VD, Ruiz RA, Götz F (2020) In silico and in vitro study of trace amines (TA) and dopamine (DOP) interaction with human alpha 1-adrenergic receptor and the bacterial adrenergic receptor QseC. Cell Physiol Biochem 54(5): 888–898.

Ma Z, Zhao X, Zhao J, Zhao Z, Wang Q, Zhang C (2020) Biologically modified polyether ether ketone as dental implant material. Front Bioeng Biotechnol 8: 620537.

Megat Badarul Hisham PN, Narmada IB, Alida A, Rahmawati D, Nugraha A,  Putranti N (2019) Effects of vitamin D in alveolar bone remodeling on osteoblast numbers and bone alkaline phosphatase expression in pregnant rats during orthodontic tooth movement. J Orofac Sci 11(2): 79–83.

Mešić E, Muratović E, Redžepagić-Vražalica L, Pervan N, Muminović AJ, Delić M, Glušac M (2021) Experimental & fem analysis of orthodontic mini-implant design on primary stability. Appl Sci 11(12): 5461.

Najeeb S, Bds ZK, Bds SZ, Bds MS (2016) Bioactivity and osseointegration of PEEK are inferior to those of titanium: A systematic review. J Oral Implantol 42(6):512–516.

Naini A, Rubianto M, Latief FDE, Gunadi A, Kristiana D, Hendrijantini N (2020) Inflammatory and immunogenic response of the tissue after application of freeze-dried hydroxyapatite gypsum puger scaffold compared to freeze-dried hydroxyapatite bovine scaffold. Contemp Clin Dent 11(4): 371–375.

Nayak UK, Malviya N (2011) Role of mini-implants in orthodontics. Int J Oral Implantol Clin Res 2(3): 126–134.

Ntolou P, Tagkli A, Pepelassi E (2018) Factors related to the clinical application of orthodontic mini-implants. J Int Oral Health 10(3): 110.

Oka S, Li X, Zhang F (2020) MicroRNA-21 facilitates osteoblast activity. Biochem Biophys Rep 25: 100894.

Papathanasiou I, Kamposiora P, Papavasiliou G, Ferrari M (2020) The use of PEEK in digital prosthodontics: A narrative review. BMC Oral Health 20(1): 217.

Peng XB, Zhang Y, Wang YQ, He Q, Yu Q (2019) IGF-1 and BMP-7 synergistically stimulate articular cartilage repairing in the rabbit knees by improving chondrogenic differentiation of bone-marrow mesenchymal stem cells. J Cell Biochem 120(4): 5570–5582.

Prahasanti C, Nugraha AP, Kharisma VD, Ansori AN, Devijanti R, Ridwan TP, Ramadhani NF, Narmada IB, Ardani IG, Noor TN (2021) A bioinformatic approach of hydroxyapatite and polymethylmethacrylate composite exploration as dental implant biomaterial. J Pharm Pharmacogn Res 9(5): 746–754.

Prahasanti C, Nugraha AP, Saskianti T, Suardita K, Riawan W, Ernawat DS (2020) Exfoliated human deciduous tooth stem cells incorporating carbonate apatite scaffold enhance BMP-2, BMP-7 and attenuate MMP-8 expression duringinitial alveolar bone remodeling in Wistar rats (Rattus norvegicus). Clin Cosmet Investig Dent 12: 79–85.

Purnama YHC, Mastutik G, Putra ST (2018) Increased activity of mature osteoblast from rat bone marrow mesenchymal stem cells in osteogenic medium exposed to melatonin. Fol Med Indones 54(4): 282–288.

Ramadhani NF, Nugraha AP, Rahmadani D, Puspitaningrum MS, Rizqianti Y, Kharisma VD, Noor TNEBTA, Ridwan RD, Ernawati DS, Nugraha AP (2022) Anthocyanin, tartaric acid, ascorbic acid of roselle flower (Hibiscus sabdariffa L.) for immunomodulatory adjuvant therapy in oral manifestation coronavirus disease-19: An immunoinformatic approach. J Pharm Pharmacogn Res 10(3): 418–428.

Rose PW, Prlić A, Altunkaya A, Bi C, Bradley AR, Christie CH, Costanzo LD, Duarte JM, Dutta S, Feng Z, Green RK (2017) The RCSB protein data bank: Integrative view of protein, gene and 3D structural information. Nucleic Acids Res 45(D1): D271–D281.

Samirah, Budiatin AS, Mahyudin F, Khotib J (2021) Fabrication and characterization of bovine hydroxyapatite-gelatin-alendronate scaffold cross-linked by glutaraldehyde for bone regeneration. J Basic Clin Physiol Pharmacol 32(4): 555–560.

Sheoran L, Kumar P, Kumar S, Ulla ST, Hussain F (2021) Implants in orthodontics: A brief review. IP Indian J Orthod Dentofacial Res 7(1): 45–48.

Simangunsong S, Muttaqin Z, Tampubolon IA (2018) Description of malocclusion in Batak students based on dental aesthetic index [Indonesian]. Prima JODS 1(1): 40–48.

Sitasari PI, Narmada IB, Hamid T, Triwardhani A, Nugraha AP, Rahmawati D (2020) East Java green tea methanolic extractcan enhance RUNX2 and osterixexpression during orthodontic tooth movement in vivo. J Pharm Pharmacogn Res 8(4): 290–298.

Syada AN, Kurniawan FK, Wibowo D (2017) Comparison of severity levels and levels of orthodontic treatment needs using the malalignment index overview in junior high schools that have school health units and junior high schools that do not have UKS [Indonesian]. Jur Ked Gigi 2(1): 78–83.

Wang X, Mei L, Jiang X, Jin M, Xu Y, Li J, Li X, Meng Z, Zhu J, Wu F (2021) Hydroxyapatite-coated titanium by micro-arc oxidation and steam-hydrothermal treatment promotes osseointegration. Front Bioeng Biotechnol 9: 625877.

Valenti MT, Dalle Carbonare L, Mottes M (2016) Osteogenic differentiation in healthy and pathological conditions. Int J Mol Sci 18(1): 41.

Vieira-Andrade RG, Paiva S, Marques LS (2015) Impact of malocclusions on quality of life from childhood to adulthood. Iss Contemp Orthod 3: 39–55.

Zhou M, Geng YM, Li SY, Yang XB, Che YJ, Pathak JL, Wu G (2019) Nanocrystalline hydroxyapatite-based scaffold adsorbs and gives sustained release of osteoinductive growth factor and facilitates bone regeneration in mice ectopic model. Journal of Nanomaterials 2019: 1202159.

Zogheib T, Walter-Solana A, De la Iglesia F, Espinar E, Gil J, Puigdollers A (2021) Do titanium mini-implants have the same quality of finishing and degree of contamination before and after different manipulations? An in vitro study. Metals 11(2): 245.

© 2022 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

Multi-epitope spike glycoprotein vaccine for SARS-CoV-2

J. Pharm. Pharmacogn. Res., vol. 10, no. 3, pp. 445-458, May-June 2022.

DOI: https://doi.org/10.56499/jppres21.1210_10.3.445

Original Article

Development of a multi-epitope spike glycoprotein vaccine to combat SARS-CoV-2 using the bioinformatics approach

[Desarrollo de una vacuna de glicoproteína spike multiepítopo para combatir el SARS-CoV-2 utilizando el enfoque bioinformático]

Aamir Shehzad1, Christijogo Sumartono2, Jusak Nugraha3, Helen Susilowati4, Andi Yasmin Wijaya4, Hafiz Ishfaq Ahmad5, Muhammad Kashif6, Wiwiek Tyasningsih7, Fedik Abdul Rantam1,4*

1Virology and Immunology Laboratory, Division of Microbiology, Faculty of Veterinary Medicine, Airlangga University, Surabaya, East Java, 60115, Indonesia.

2Anasthesiology and Reanimation Department, Dr. Soetomo Gerneral Hospital and Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.

3Clinical Pathology Department, Dr. Soetomo Gerneral Hospital and Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia.

4Research Center for Vaccine Technology and Development, Institute of Tropical Disease, Universitas Airlangga, Surabaya, Indonesia.

5Department of Animal Breeding and Genetics, University of Veterinary and Animal Sciences, Ravi Campus, Pattoki, Punjab, Pakistan.

6Department of Biomedical Engineering, Science and Technology, Universitas Airlangga, Surabaya, Indonesia.

7Bacteriology and Mycology Laboratory, Department of Microbiology, Faculty of Veterinary Medicine, Universitas Airlangga, Surabaya, 60132, Indonesia.

*E-mail: fedik-a-r@fkh.unair.ac.id

Abstract

Context: The current COVID-19 pandemic has significantly impacted health and socio-economic status worldwide. The only way to combat this situation is to develop an effective vaccine and immunize people around the globe.

Aims: To construct a multi-epitope spike glycoprotein-based vaccine from the SARS-CoV-2 Surabaya isolate using a bioinformatics approach.

Methods: The spike protein was submitted to IEDB, VaxiJen, AllerTOP, and ToxinPred webservers to predict antigenic, non-allergic, non-toxic, B- and T-cell epitopes. To develop a multi-epitope vaccine, an adjuvant cholera toxin B subunit was linked to B-cell and B-cell with T-cell through EAAAK and GPGPG linkers, respectively. The designed vaccine 3D structure development, refinement, and validation were done through PHYRE2, Galaxy Refine, and RAMPAGE webservers. Moreover, the Cluspro-2.0 webserver was used for the molecular docking of the vaccine designed with TLR3. The vaccine+TLR3 complex was docked with Surfactant protein A as a control to validate the docking results. Finally, immune-simulation and in silico cloning of the vaccine were carried out by C-ImmSim webserver and SnapGene software, respectively.

Results: A multi-epitopic vaccine containing B and T-cell was developed using 392 amino acids with a molecular weight of 40825.59 Da. The docking and immunogenicity results of the vaccine met all established parameters for constructing a quality vaccine. Furthermore, the optimized sequence of the vaccine was successfully cloned in expression vector pET 28 a (+) that yielded a colon of 2724 bp.

Conclusions: The vaccine’s immunogenicity demonstrates its effectiveness against SARS-CoV-2 infection. Further confirmatory testing may therefore be performed as soon as possible in the public interest.

Keywords: in silico; public health; SARS-CoV-2; spike protein; TLR3-receptor.

Resumen

Contexto: La actual pandemia de COVID-19 ha afectado significativamente la salud y el estado socioeconómico en todo el mundo. La única forma de combatir esta situación es desarrollar una vacuna eficaz e inmunizar a las personas en todo el mundo.

Objetivos: Construir una vacuna basada en glicoproteína de pico de múltiples epítopos a partir del aislado SARS-CoV-2 Surabaya utilizando un enfoque bioinformático.

Métodos: La proteína de pico se envió a los servidores web IEDB, VaxiJen, AllerTOP y ToxinPred para predecir epítopos antigénicos, no alérgicos, no tóxicos, de células B y T. Para desarrollar una vacuna multiepítopo, se unió una subunidad B de la toxina del cólera adyuvante a la célula B y una célula B a una célula T a través de conectores EAAAK y GPGPG, respectivamente. El desarrollo, el refinamiento y la validación de la estructura 3D de la vacuna diseñada se realizaron a través de los servidores web PHYRE2, Galaxy Refine y RAMPAGE. Además, se utilizó el servidor web Cluspro-2.0 para el acoplamiento molecular de la vacuna diseñada con TLR3. El complejo vacuna + TLR3 se acopló con la proteína A del tensioactivo como control para validar los resultados del acoplamiento. Finalmente, la inmunosimulación y la clonación in silico de la vacuna se llevaron a cabo mediante el servidor web C-ImmSim y el software SnapGene, respectivamente.

Resultados: Se desarrolló una vacuna multiepitópica que contenía células B y T utilizando 392 aminoácidos con un peso molecular de 40825,59 Da. Los resultados de acoplamiento e inmunogenicidad de la vacuna cumplieron con todos los parámetros establecidos para construir una vacuna de calidad. Además, la secuencia optimizada de la vacuna se clonó con éxito en el vector de expresión pET 28 a (+) que produjo un colon de 2724 pb.

Conclusiones: La inmunogenicidad de la vacuna demuestra su eficacia contra la infección por SARS-CoV-2. Por lo tanto, se pueden realizar más pruebas de confirmación lo antes posible en interés público.

Palabras Clave: in silico; proteína de punta; receptor TLR3; salud pública; SARS-CoV-2.

This image has an empty alt attribute; its file name is jppres_pdf_free.png
Citation Format: Shehzad A, Sumartono C, Nugraha J, Susilowati H, Wijaya AY, Ahmad HI, Kashif M, Tyasningsih W, Rantam FA (2022) Development of a multi-epitope spike glycoprotein vaccine to combat SARS-CoV-2 using the bioinformatics approach. J Pharm Pharmacogn Res 10(3): 445–458.https://doi.org/10.56499/jppres21.1210_10.3.445
References

Abraham Peele K, Srihansa T, Krupanidhi S, Ayyagari VS, Venkateswarulu TC (2021) Design of multi-epitope vaccine candidate against SARS-CoV-2: A in-silico study. J Biomol Struct Dyn 39(10): 3793–3801.

Ahmad B, Ashfaq UA, Rahman MU, Masoud MS, Yousaf MZ (2019) Conserved B and T cell epitopes prediction of Ebola virus glycoprotein for vaccine development: An immuno-informatics approach. Microb Pathog 132: 243–253.

Ahmad I, Ali SS, Zafar B, Hashmi HF, Shah I, Khan S, Suleman M, Khan M, Ullah S, Ali S, Khan J (2020) Development of multi-epitope subunit vaccine for protection against the norovirus’ infections based on computational vaccinology. J Biomol Struct Dyn 9: 1–12.

Ali M, Pandey RK, Khatoon N, Narula A, Mishra A, Prajapati VK (2017) Exploring dengue genome to construct a multi-epitope-based subunit vaccine by utilizing immunoinformatics approach to the battle against dengue infection. Sci Rep 7(1): 9232.

Amer H, Alqahtani AS, Alaklobi F, Altayeb J, Memish ZA (2018) Healthcare worker exposure to Middle East respiratory syndrome coronavirus (MERS-CoV): Revision of screening strategies urgently needed. Int J Infect Dis 71: 113–116.

Artimo P, Jonnalagedda M, Arnold K, Baratin D, Csardi G, De Castro E, Duvaud S, Flegel V, Fortier A, Gasteiger E, Grosdidier A (2012) ExPASy: SIB bioinformatics resource portal. Nucleic Acids Res 40(W1): W597–W603.

Arumugam S, Varamballi P (2021) In-silico design of envelope-based multi-epitope vaccine candidate against Kyasanur forest disease virus. Sci Rep 11(1): 17118.

Ashfaq UA, Ahmed B (2016) De novo structural modeling and conserved epitopes prediction of Zika virus envelop protein for vaccine development. Viral Immunol 29(7): 436–443.

Baruah V, Bose S (2020) Immunoinformatics‐aided identification of T cell and B cell epitopes in the surface glycoprotein of 2019‐nCoV. J Med Virol 92(5): 495–500.

Chang KY, Yang JR (2013) Analysis and prediction of highly effective antiviral peptides based on random forests. PloS One 8(8): e70166.

Chukwudozie OS, Chukwuanukwu RC, Iroanya OO, Eze DM, Duru VC, Dele-Alimi TO, Kehinde BD, Bankole TT, Obi PC, Okinedo EU (2020) Attenuated subcomponent vaccine design targeting the SARS-CoV-2 nucleocapsid phosphoprotein RNA binding domain: In silico analysis. J Immunol Res 2020: 2837670.

Chukwudozie OS, Gray CM, Fagbayi TA, Chukwuanukwu RC, Oyebanji VO, Bankole TT, Adewole RA, Daniel EM (2021) Immuno-informatics design of a multimeric epitope peptide-based vaccine targeting SARS-CoV-2 spike glycoprotein. Plos One 16(3): e0248061.

Cockrell AS, Johnson JC, Moore IN, Liu DX, Bock KW, Douglas MG, Graham RL, Solomon J, Torzewski L, Bartos C, Hart R (2018) A spike-modified Middle East respiratory syndrome coronavirus (MERS-CoV) infectious clone elicits mild respiratory disease in infected rhesus macaques. Sci Rep 8(1): 10727.

Dar HA, Waheed Y, Najmi MH, Ismail S, Hetta HF, Ali A, Muhammad K (2020) Multiepitope subunit vaccine design against COVID-19 based on the spike protein of SARS-CoV-2: An in silico analysis. J Immunol Res 2020: 8893483.

Dimitrov I, Flower DR, Doytchinova I (2013) AllerTOP-a server for in silico prediction of allergens. BMC Bioinform 14(suppl. 6): S4.

Dong R, Chu Z, Yu F, Zha Y (2020) Contriving multi-epitope subunit of vaccine for COVID-19: Immunoinformatics approaches. Front Immunol 11:1784.

Doytchinova IA, Flower DR (2007) VaxiJen: a server for prediction of protective antigens, tumour antigens and subunit vaccines. BMC Bioinform 8(1): 4.

Gasteiger E, Hoogland C, Gattiker A, Wilkins MR, Appel RD, Bairoch A (2005) Protein identification and analysis tools on the ExPASy server. The Proteomics Protocols Handbook, pp. 571–607.

Geourjon C, Deleage G (1995) SOPMA: Significant improvements in protein secondary structure prediction by consensus prediction from multiple alignments. Bioinform 11(6): 681–684.

Gupta S, Kapoor P, Chaudhary K, Gautam A, Kumar R, Open-Source Drug Discovery Consortium, Raghava GP (2013) In silico approach for predicting toxicity of peptides and proteins. PloS One 8(9): e73957.

Houston S, Lithgow KV, Osbak KK, Kenyon CR, Cameron CE (2018) Functional insights from proteome-wide structural modeling of Treponema pallidum subspecies pallidum, the causative agent of syphilis. BMC Struct Biol 18(1): 7.

Hui DS, Azhar EI, Kim YJ, Memish ZA, Oh MD, Zumla A (2018) Middle East respiratory syndrome coronavirus: risk factors and determinants of primary, household, and nosocomial transmission. Lancet Infect Dis 18(8): e217-27.

Ikai A (1980) Thermostability and aliphatic index of globular proteins. J Biochem 88(6): 1895-1898.

Indriani R (2001) Antibody response and protection of inactivated-local isolate vaccine for infectious bronchitis in laying chicken. J IImTer Vet 6(2): 134–140.

Jespersen MC, Peters B, Nielsen M, Marcatili P (2017) BepiPred-2.0: improving sequence-based B-cell epitope prediction using conformational epitopes. Nucleic Acids Res 45(W1): W24–W29.

Jyotisha, Singh S, Qureshi IA (2020) Multi-epitope vaccine against SARS-CoV-2 applying immunoinformatics and molecular dynamics simulation approaches. J Biomol Struct Dyn 6: 1–17.

Kamens J (2015) The Addgene repository: an international nonprofit plasmid and data resource. Nucleic Acids Res 43(D1): D1152–D1157.

Kathwate GH (2022) In silico design and characterization of multi-epitopes vaccine for SARS-CoV2 from its spike protein. Int J Pept Res Ther 28(1): 37.

Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJ (2015) The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc 10(6): 845–858.

Khalil I, Omer I, Farh IZ, Mohamed HA, Elsharif HA, Mohamed AA, Awad-Elkareem MA, Salih MA (2018) Design of an epitope-based peptide vaccine against Cryptococcus neoformans. BioRxiv [Preprint]. doi: https://doi.org/10.1101/434779

Ko J, Park H, Heo L, Seok C (2012) GalaxyWEB server for protein structure prediction and refinement. Nucleic Acids Res 40(W1): W294–W297.

Lan J, Ge J, Yu J, Shan S, Zhou H, Fan S, Zhang Q, Shi X, Wang Q, Zhang L, Wang X (2020) Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581(7807): 215–220.

Lu R, Zhao X, Li J, Niu P, Yang B, Wu H, Wang W, Song H, Huang B, Zhu N, Bi Y, Ma X, Zhan F, Wang L, Hu T, Zhou H, Hu Z, Zhou W, Zhao L, Chen J, Meng Y, Wang J, Lin Y, Yuan J, Xie Z, Ma J, Liu WJ, Wang D, Xu W, Holmes EC, Gao GF, Wu G, Chen W, Shi W, Tan W (2020) Genomic characterisation and epidemiology of 2019 novel coronavirus: Implications for virus origins and receptor binding. Lancet 395: 565–574.

Martínez-Flores D, Zepeda-Cervantes J, Cruz-Reséndiz A, Aguirre-Sampieri S, Sampieri A, Vaca L (2021) SARS-CoV-2 vaccines based on the spike glycoprotein and implications of new viral variants. Front Immunol 12: 701501.

McCartney S, Vermi W, Gilfillan S, Cella M, Murphy TL, Schreiber RD, Murphy KM, Colonna M (2009) Distinct and complementary functions of MDA5 and TLR3 in poly (I: C)-mediated activation of mouse NK cells. J Exp Med 206(13): 2967–2976.

McKee AS, Munks MW, Marrack P (2007) How do adjuvants work? Important considerations for new generation adjuvants. Immunity 27(5): 687–690.

Naveed M, Tehreem S, Arshad S, Bukhari SA, Shabbir MA, Essa R, Ali N, Zaib S, Khan A, Al-Harrasi A, Khan I (2021) Design of a novel multiple epitope-based vaccine: An immunoinformatics approach to combat SARS-CoV-2 strains. J Infect Public Health 14(7): 938–946.

O’Hagan DT, De Gregorio E (2009) The path to a successful vaccine adjuvant– ‘the long and winding road’. Drug Discov Today 14(11-12): 541–551.

Oany AR, Ahmad SA, Hossain MU, Jyoti TP (2015) Identification of highly conserved regions in L-segment of Crimean–Congo hemorrhagic fever virus and immunoinformatic prediction about potential novel vaccine. Adv Appl Bioinform Chem 8: 1–10.

Oany AR, Emran AA, Jyoti TP (2014) Design of an epitope-based peptide vaccine against spike protein of human coronavirus: an in-silico approach. Drug Des Devel Ther 8: 1139–1149.

Olvera A, Noguera-Julian M, Kilpelainen A, Romero-Martín L, Prado JG, Brander C (2020) SARS-CoV-2 consensus-sequence and matching overlapping peptides design for COVID19 immune studies and vaccine development. Vaccines 8(3): 444.

Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z (2020) Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 11(1): 2144.

Phan AT, Goldrath AW, Glass CK (2017) Metabolic and epigenetic coordination of T cell and macrophage immunity. Immunity 46(5): 714–729.

Poran A, Harjanto D, Malloy M, Arieta CM, Rothenberg DA, Lenkala D, van Buuren MM, Addona TA, Rooney MS, Srinivasan L, Gaynor RB (2020) Sequence-based prediction of SARS-CoV-2 vaccine targets using a mass spectrometry-based bioinformatics predictor identifies immunogenic T cell epitopes. Genome Med 12(1): 70.

Prajapat M, Sarma P, Shekhar N, Avti P, Sinha S, Kaur H, Kumar S, Bhattacharyya A, Kumar H, Bansal S, Medhi B (2020) Drug targets for corona virus: A systematic review. Indian J Pharmacol 52(1): 56–65.

Raoult D, Zumla A, Locatelli F, Ippolito G, Kroemer G (2020) Coronavirus infections: Epidemiological, clinical and immunological features and hypotheses. Cell Stress 4(4): 66–75.

Reche PA, Fernandez-Caldas E, Flower DR, Fridkis-Hareli M, Hoshino Y (2014) Peptide-based immunotherapeutics and vaccines. J Immunol Res2014: 256784.

Sadat SM, Aghadadeghi MR, Yousefi M, Khodaei A, Larijani MS, Bahramali G (2021) Bioinformatics analysis of SARS-CoV-2 to approach an effective vaccine candidate against COVID-19. Mol Biotechnol 63(5): 389–409.

Safavi A, Kefayat A., Mahdevar E, Abiri A, Ghahremani F (2020) Exploring the out of sight antigens of SARS-CoV-2 to design a candidate multi-epitope vaccine by utilizing immunoinformatics approaches. Vaccine 38(48): 7612–7628.

Sarma P, Shekhar N, Prajapat M, Avti P, Kaur H, Kumar S, Singh S, Kumar H, Prakash A, Dhibar DP, Medhi B (2021) In-silico homology assisted identification of inhibitor of RNA binding against 2019-nCoV N-protein (N terminal domain). J Biomol Struct Dyn 39(8): 2724–2732.

Shokeen K, Pandey S, Shah M, Kumar S (2020) Insight towards the effect of the multibasic cleavage site of SARS-CoV-2 spike protein on cellular proteases. BioRxiv [Preprint].doi:https://doi.org/10.1101/2020.04.25.061507.

Singh A, Thakur M, Sharma LK, Chandra K (2020) Designing a multi-epitope peptide-based vaccine against SARS-CoV-2. Sci Rep 10(1): 16219.

Srivastava S, Kamthania M, Kumar Pandey R, Kumar Saxena A, Saxena V, Kumar Singh S, Kumar Sharma R, Sharma N (2019) Design of novel multi-epitope vaccines against severe acute respiratory syndrome validated through multistage molecular interaction and dynamics. J Biomol Struct Dyn 37(16): 4345–4360.

Tahir Ul Qamar M, Rehman A, Tusleem K, Ashfaq UA, Qasim M, Zhu X, Fatima I, Shahid F, Chen LL (2020a) Designing of a next generation multi-epitope-based vaccine (MEV) against SARS-COV-2: Immunoinformatics and in silico approaches. PloS One 15(12): e0244176.

Tahir Ul Qamar M, Shokat Z, Muneer I, Ashfaq UA, Javed H, Anwar F, Bari A, Zahid B, Saari N (2020b) Multiepitope-based subunit vaccine design and evaluation against respiratory syncytial virus using reverse vaccinology approach. Vaccines 8(2): 288.

Tahir Ul Qamar MT, Bari A, Adeel MM, Maryam A, Ashfaq UA, Du X, Muneer I, Ahmad HI, Wang J (2018) Peptide vaccine against chikungunya virus: Immuno-informatics combined with molecular docking approach. J Transl Med 16(1): 298.

Tahir Ul Qamar MT, Saleem S, Ashfaq UA, Bari A, Anwar F, Alqahtani S (2019) Epitope‐based peptide vaccine design and target site depiction against Middle East Respiratory Syndrome Coronavirus: An immune-informatics study. J Transl Med 17(1): 362.

Wan Y, Shang J, Graham R, Baric RS, Li F (2020) Receptor recognition by the novel coronavirus from Wuhan: An analysis based on decade-long structural studies of SARS coronavirus. Virol J94(7): e00127-20.

Weiss SR, Navas-Martin S (2005) Coronavirus pathogenesis and the emerging pathogen severe acute respiratory syndrome coronavirus. Microbiol Mol Biol Rev 69(4): 635–664.

WHO (2021) World Health Organization. https://covid19.who.int/ [Consulted September 27, 2021].

Wu JT, Leung K, Leung GM (2020) Nowcasting and forecasting the potential domestic and international spread of the 2019-nCoV outbreak originating in Wuhan, China: A modelling study. Lancet 395(10225): 689–697.

Yang Z, Bogdan P, Nazarian S (2021) An in silico deep learning approach to multi-epitope vaccine design: A SARS-CoV-2 case study. Sci Rep 11(1): 3238.

Zeng L, Li D, Tong W, Shi T, Ning B (2021) Biochemical features and mutations of key proteins in SARS-CoV-2 and their impacts on RNA therapeutics. Biochem Pharmacol189: 114424.

Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD (2020) A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579 (7798): 270–273.

Zhu X, Liu Q, Du L, Lu L, Jiang S (2013) Receptor-binding domain as a target for developing SARS vaccines. J Thorac Dis 5(Suppl 2): S142–S148.

© 2022 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

Hydroxyapatite-polymethylmethacrylate dental implant in silico


J Pharm Pharmacogn Res 9(5): 746-754, 2021.

Original article

A bioinformatic approach of hydroxyapatite and polymethylmethacrylate composite exploration as dental implant biomaterial

[Un enfoque bioinformático de la exploración con compuestos de hidroxiapatita y polimetilmetacrilato como biomaterial de implantes dentales]

Chiquita Prahasanti1, Alexander Patera Nugraha1,2*, Viol Dhea Kharisma3, Arif Nur Muhammad Ansori4, Rini Devijanti Ridwan1, Tansza Permata Setiana Putri1, Nastiti Faradilla Ramadhani5, Ida Bagus Narmada1,2, I Gusti Aju Wahju Ardani1,2, Tengku Natasha Eleena Binti Ahmad Noor6

1Dental Implant Research Group, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

2Department of Orthodontic, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia.

3Department of Biology, Faculty of Mathematic and Natural Science, Brawijaya University, Malang Indonesia.

4Department of Biology, Faculty of Science and Technology, Universitas Airlangga, Surabaya, Indonesia.

5Graduate Student of Dental Health Science, Universitas Airlangga, Surabaya, Indonesia.

6Dental Officer of 609 Armed Forces Dental Clinic, Kuching, Sarawak, Malaysia.

*E-mail: alexander.patera.nugraha@fkg.unair.ac.id

Abstract

Context: The most common biomaterial used for dental implants is titanium. However, the release of metal ions and the risk of allergic reactions to metals that may occur in some patients cannot be avoided. Hydroxyapatite-polymethylmethacrylate (HA-PMMA) composite biomaterials are proposed to have potential as dental implant biomaterials due to their mechanical, chemical, and biological properties. HA-PMMA may induce osseointegration, biocompatible, less allergic reactions, and no metal ions released. In addition, HA-PMMA can be obtained from Indonesia’s abundant natural resources.

Aims: To explore HA-PMMA composites through molecular docking as a biomaterial candidate for dental implants in silico.

Methods: Structure data format (sdf), molecular weight, and identity number (CID) of HA-PMMA ligand samples were obtained from PubChem database and minimized through OpenBabel. 3D structure, selection method, resolution, atom count, weight, sequence length, and ID protein BMP2, BMP4, BMP7, alkaline phosphatase (AP), osteonectin, osteopontin, and osteocalcin on RCSB-PDB native ligand and water sterilization on PyMol were carried out with the aim of to maximize the formation of binding affinity during molecular docking simulations.

Results: HA-PMMA composites can enhance the activity of proteins associated with osseointegration such as BMP-2/4/7, AP, osteocalcin, osteonectin, and osteopontin in silico. HA-PMMA composites have the strongest binding to osteonectin and are predicted to enhance the AP activity in silico.

Conclusions: HA-PMMA composites are potential candidates for dental implant biomaterials with the osteointegration ability through binding with BMP-2/4/7, AP, osteocalcin, osteonectin, and osteopontin in silico.

Keywords: biomaterials; composite; human well-being; hydroxyapatite-polymethylmethacrylate; in silico; osseointegration.

This image has an empty alt attribute; its file name is jppres_pdf_free.png
Resumen

Contexto: El biomaterial más común utilizado para implantes dentales es el titanio. Con este no se evita la liberación de iones metálicos y el riesgo de reacciones alérgicas a los metales que pueden ocurrir en algunos pacientes. Se propone que los biomateriales compuestos de hidroxiapatita-polimetilmetacrilato (HA-PMMA) tienen un potencial como biomateriales de implantes dentales debido a sus propiedades mecánicas, químicas y biológicas. HA-PMMA puede inducir osteointegración, reacciones biocompatibles, menos alérgicas y sin liberación de iones metálicos.

Objetivos: Explorar los implantes HA-PMMA a través del acoplamiento molecular como biomaterial candidato para implante dental in silico.

Métodos: Formato de datos de estructura (sdf), peso molecular y número de identidad (CID) de muestras de ligando HA-PMMA se obtuvieron de PubChem y se minimizaron a través de OpenBabel. Estructura 3D, método de selección, resolución, recuento de átomos, peso, longitud de secuencia e identificación de proteínas BMP2, BMP4, BMP7, fosfatasa alcalina (AP), osteonectina, ostepontina y osteocalcina en ligando nativo RCSB-PDB y esterilización de agua en PyMol fueron desarrollados con el objetivo de maximizar la formación de afinidad de unión durante las simulaciones de acoplamiento molecular.

Resultados: Los implantes de HA-PMMA pueden potenciar la actividad de proteínas asociadas con la osteointegración como BMP-2/4/7, AP, osteocalcina, osteonectina y osteopontina in silico. Los implantes de HA-PMMA se unen fuertemente a la osteonectina y podrían mejorar la actividad AP in silico.

Conclusiones: Los implantes de HA-PMMA son candidatos potenciales para implantes dentales con capacidad de osteointegración por la unión con BMP-2/4/7, AP, osteocalcina, osteonectina y osteopontina in silico.

Palabras Clave: bienestar humano; biomateriales; hidroxiapatita-polimetilmetacrilato; implante; in silico; osteointegración.

This image has an empty alt attribute; its file name is jppres_pdf_free.png
Citation Format: Prahasanti C, Nugraha AP, Kharisma VD, Ansori ANM, Ridwan RD, Putri TPS, Narmada IB, Ardani IGAW, Ramadhani NF, Noor TNEBA (2021) A bioinformatic approach of hydroxyapatite and polymethylmethacrylate composite exploration as dental implant biomaterial. J Pharm Pharmacogn Res 9(5): 746–754.

© 2021 Journal of Pharmacy & Pharmacognosy Research (JPPRes)

Characterization in vitro and in silico of Q10 NLCs


J Pharm Pharmacogn Res 9(5): 573-583, 2021.

Original article

Development, characterization in vitro and in silico of coenzyme Q10 loaded myristic acid with different liquid lipids nanostructured lipid carriers

[Desarrollo, caracterización in vitro e in silico de coenzima Q10 cargado de ácido mirístico con diferentes lípidos líquidos portadores de lípidos nanoestructurados]

Ni Luh Dewi Aryani1,4, Siswandono2, Wdji Soeratri3*, Dian Yulyandani Putri4, Pingky Dwi Puspitasarini4

1Doctoral Program of Pharmaceutical Sciences, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia.

2Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia.

3Department of Pharmaceutics, Faculty of Pharmacy, Airlangga University, Surabaya, Indonesia.

4Department of Pharmaceutics, Faculty of Pharmacy, University of Surabaya, Surabaya, Indonesia.

*E-mail: widji-s@ff.unair.ac.id

Abstract

Context: Nanostructured lipid carriers can enhance skin penetration of active substances. Coenzyme Q10 is a lipophilic antioxidant, that has poor skin penetration. This limitation is overcome by nanostructured lipid carriers.

Aims: To developed coenzyme Q10 nanostructured lipid carriers using myristic acid with various liquid lipids as lipid matrix by in vitro studies and in silico approach for explaining the interaction of coenzyme Q10-lipid at the molecular level.

Methods: The coenzyme Q10 nanostructured lipid carriers were prepared using myristic acid as solid lipid with oleic acid, isopropyl myristate, and isopropyl palmitate as liquid lipids using the high shear homogenization method. Then, they were evaluated in physicochemical characteristics by dynamic light scattering, differential scanning calorimetry, Fourier transforms infrared, scanning electron microscopy, spectrophotometry ultraviolet-visible, and pH meter. Furthermore, the in silico studies were conducted using AutoDock 4.2.

Results: The coenzyme Q10 nanostructured lipid carriers using myristic acid-oleic acid, myristic acid-isopropyl myristate, and myristic acid-isopropyl palmitate as lipid matrix had the mean particle size, polydispersity index, entrapment efficiency, drug loading, and pH value were less than 300 nm, less than 0.3, more than 80%, about 10%, and about 5.0, respectively. Moreover, molecular docking of coenzyme Q10 and lipid showed hydrogen and hydrophobic bonds. These results supported differential scanning calorimetry and Fourier transforms infrared results.

Conclusions: The coenzyme Q10 nanostructured lipid carriers were successfully prepared using myristic acid-oleic acid, myristic acid-isopropyl myristate, and myristic acid-isopropyl palmitate as lipid matrix as well as in silico study could be used for explaining of coenzyme Q10-lipid interaction.

Keywords: coenzyme Q10; in silico; in vitro; nanostructured lipid carriers.

This image has an empty alt attribute; its file name is jppres_pdf_free.png
Resumen

Contexto: Los portadores de lípidos nanoestructurados pueden mejorar la penetración cutánea de sustancias activas. La coenzima Q10 es un antioxidante lipofílico, que tiene poca penetración en la piel. Esta limitación se supera mediante portadores de lípidos nanoestructurados.

Objetivos: Desarrollar portadores de lípidos nanoestructurados de coenzima Q10 utilizando ácido mirístico con varios lípidos líquidos como matriz lipídica mediante estudios in vitro y enfoque in silico para explicar la interacción de la coenzima Q10-lípido a nivel molecular.

Métodos: Los portadores de lípidos nanoestructurados de coenzima Q10 se prepararon usando ácido mirístico como lípido sólido con ácido oleico, miristato de isopropilo y palmitato de isopropilo como lípidos líquidos usando el método de homogeneización de alto cizallamiento. Luego, fueron evaluados en características fisicoquímicas por dispersión dinámica de luz, calorimetría diferencial de barrido, transformadas de Fourier infrarrojas, microscopía electrónica de barrido, espectrofotometría ultravioleta-visible y pHmetro. Además, los estudios in silico se realizaron utilizando AutoDock 4.2.

Resultados: Los portadores de lípidos nanoestructurados de coenzima Q10 que utilizaron ácido mirístico-ácido oleico, ácido mirístico-miristato de isopropilo y ácido mirístico-palmitato de isopropilo como matriz lipídica tuvieron un tamaño medio de partícula, índice de polidispersidad, eficiencia de atrapamiento, carga de fármaco y valor de pH menores. de 300 nm, menos de 0,3, más del 80%, aproximadamente el 10% y aproximadamente 5,0, respectivamente. Además, el acoplamiento molecular de la coenzima Q10 y el lípido mostró enlaces hidrófobos y de hidrógeno. Estos resultados apoyaron la calorimetría de barrido diferencial y los resultados infrarrojos transformados de Fourier.

Conclusiones: Los portadores de lípidos nanoestructurados de coenzima Q10 se prepararon con éxito utilizando ácido mirístico-ácido oleico, miristato de ácido mirístico-isopropilo y ácido mirístico-palmitato de isopropilo como matriz lipídica, así como un estudio in silico que podría usarse para explicar la interacción coenzima Q10-lípido.

Palabras Clave: coenzima Q10; in silico; in vitro; portadores de lípidos nanoestructurados.

This image has an empty alt attribute; its file name is jppres_pdf_free.png
Citation Format: Aryani NLD, Siswandono, Soeratri W, Putri DY, Pingky DP (2021) Development, characterization in vitro and in silico of coenzyme Q10 loaded myristic acid with different liquid lipids nanostructured lipid carriers. J Pharm Pharmacogn Res 9(5): 573–583.

© 2021 Journal of Pharmacy & Pharmacognosy Research (JPPRes)