In silico anti-diabetic study of T. diversifolia

J. Pharm. Pharmacogn. Res., vol. 10, no. 4, pp. 571-594, July-August 2022.

Original Article

In silico ADME-T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy

[ADME-T in silico y estudio de acoplamiento molecular de fitoconstituyentes de Tithonia diversifolia (Hemsl.) A. Gray en varias dianas de nefropatía diabética]

Oktavia Rahayu Adianingsih*, Uswatun Khasanah, Kevin Diagonsa Anandhy, Valentina Yurina

Department of Pharmacy, Faculty of Medicine, Universitas Brawijaya, Malang, 65145, Indonesia.



Context: Tithonia diversifolia (Hemsl.) A. Grayhas been known for treatment of diabetes mellitus, yet its mechanism as anti-diabetic has not been defined. There are various therapeutic targets for diabetes and its complication such as diabetic nephropathy.

Aims: To investigate the mechanism of phytoconstituents in Tithonia diversifolia to various targets of diabetic nephropathy and predict the pharmacokinetic profile such as absorption, distribution, metabolism, elimination, and toxicity (ADME-T).

Methods: Eighteen phytoconstituents in Tithonia diversifolia were analyzed for drug-likeness. The molecular docking of molecules was performed to protein targets, then its molecular interaction was determined. ADME-T properties were predicted using three different web servers.

Results: Drug-likeness analysis showed that all the phytoconstituents were within the range set by Lipinski’s rule of five. This study showed that Tithonia diversifolia have potential as a candidate for diabetic nephropathy therapy agent with various mechanisms by inhibiting α-glucosidase, ACE, ALR, DPP-4, LMW-PTP, RAGE, SGLT2, SUR1, and an analog of PPAR-γ. 5-Caffeoylquinic acid, catechin, diversifolin, hispidulin, tagitinin A, tagitinin C, tagitinin F, tithonine, and tirotundin were phytoconstituents with a high binding affinity to several proteins. β-gurjunene, tagitinin A,tagitinin C, tagitinin F, and tirotundin were predicted to have a better ADME-T properties than other compounds. In summary, tagitinin A, tagitinin C, tagitinin F, and tirotundin were showed the high binding affinity to various diabetes-related proteins and have a good ADME-T profile.

Conclusions: This study suggests that Tithonia diversifolia constituents have potential properties as an anti-diabetic nephropathy agent, and further studies to analyze its potency are required.

Keywords: diabetes; insulin leaf; nephropathy; Tithonia diversifolia.

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Contexto: Tithonia diversifolia (Hemsl.) A. Gray ha sido conocida para el tratamiento de la diabetes mellitus, pero su mecanismo como antidiabético no ha sido definido. Existen varios objetivos terapéuticos para la diabetes y sus complicaciones, como la nefropatía diabética.

Objetivos: Investigar el mecanismo de los fitoconstituyentes en Tithonia diversifolia para varias dianas de la nefropatía diabética y predecir el perfil farmacocinético como la absorción, distribución, metabolismo, eliminación y toxicidad (ADME-T).

Métodos: Se analizaron 18 fitoconstituyentes en Tithonia diversifolia para determinar su similitud con las drogas. Se realizó el acoplamiento molecular de moléculas a dianas proteicas, luego se determinó su interacción molecular. Las propiedades de ADME-T se predijeron utilizando tres servidores web diferentes.

Resultados: El análisis de semejanza con las drogas mostró que todos los fitoconstituyentes estaban dentro del rango establecido por la regla de cinco de Lipinski. Este estudio mostró que Tithonia diversifolia tiene potencial como candidato para el tratamiento de la nefropatía diabética con varios mecanismos mediante la inhibición de la α-glucosidasa, ACE, ALR, DPP-4, LMW-PTP, RAGE, SGLT2, SUR1 y un análogo de PPAR-γ. Ácido 5-cafeoilquínico, catequina,  diversifolina, hispidulina, tagitinina A, tagitinina C, tagitinina F, titonina y tirotundina fueron fitoconstituyentes con una alta afinidad de unión a varias proteínas. Se predijo que β-gurjunene, tagitinina A, tagitinina C, tagitinina F y tirotundina tenían mejores propiedades ADME-T que otros compuestos. En resumen, tagitinina A, tagitinina C, tagitinina F y tirotundina mostraron una alta afinidad de unión a varias proteínas relacionadas con la diabetes y tienen un buen perfil ADME-T.

Conclusiones: Este estudio sugiere que los componentes de Tithonia diversifolia tienen propiedades potenciales como agente anti-nefropatía diabética, y se requieren más estudios para analizar su potencia.

Palabras Clave: diabetes; hoja de insulina; nefropatía; Tithonia diversifolia.

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Citation Format: Adianingsih OR, Khasanah U, Anandhy KD, Yurina V (2022) In silico ADME-T and molecular docking study of phytoconstituents from Tithonia diversifolia (Hemsl.) A. Gray on various targets of diabetic nephropathy. J Pharm Pharmacogn Res 10(4): 571–594.

Adebayo JO, Balogun EA, Oyeleke S (2009) Toxicity study of the aqueous extract of Tithonia diversifolia leaves using selected biochemical parameters in rats. Pharmacogn Res 1(3): 143–147.

Adianingsih OR, Kharisma VD (2019) Study of B cell epitope conserved region of the Zika virus envelope glycoprotein to develop multi-strain vaccine. J Appl Pharm Sci 9(1): 98–103.

Adianingsih OR, Lyrawati D, Samsu N (2016) Advanced glycation end products (AGEs) antibody protects against AGEs-induced apoptosis and NF-ĸB p65 subunit overexpression in rat glomerular culture. J Trop Life Sci 6(3): 176–183.

Aittoniemi J, Fotinou C, Craig TJ, De Wet H, Proks P, Ashcroft FM (2009) SUR1: A unique ATP-binding cassette protein that functions as an ion channel regulator. Philos Trans R Soc B Biol Sci 364(1514): 257–267.

Alicic RS, Rooney MT, Tuttle KR (2017) Diabetic kidney disease: challenges, progress, and possibilities. Clin J Am Soc Nephrol 12(12): 2032–2045.

Amanatie ES (2015) Structure elucidation of the leaf of Tithonia diversifolia (Hemsl) Gray. J Sains Mat 23(4): 101–106.

Antony P, Vijayan R (2015) Identification of novel aldose reductase inhibitors from spices: a molecular docking and simulation study. PLoS One 10(9): e0138186.

Arfin S, Siddiqui GA, Naeem A, Moin S (2018) Inhibition of advanced glycation end products by isoferulic acid and its free radical scavenging capacity: an in vitro and molecular docking study. Int J Biol Macromol 118: 1479–1487.

Attique SA, Hassan M, Usman M, Atif RM, Mahboob S, Al-Ghanim KA, Bilal M, Nawaz MZ (2019) A molecular docking approach to evaluate the pharmacological properties of natural and synthetic treatment candidates for use against hypertension. Int J Environ Res Public Health 16(6): 923.

Awaluddin R, Muhtadi WK, Chabib L, Ikawati Z, Martien R, Ismail H (2017) Molecular docking and ADME-toxicity studies of potential compounds of medicinal plants grown in Indonesia as an anti-rheumatoid arthritis. AIP Conf Proc 1823: 020033.

Babatomiwa K, Joseph AO, Damilohun SM, Olaposi IO, Niyi SA (2020) Virtual screening and pharmacokinetic studies of potential MAO-B inhibitors from traditional Chinese medicine. J Biol Eng Res Rev 7(1): 8–15.

Barr AJ (2010) Protein tyrosine phosphatases as drug targets: strategies and challenges of inhibitor development. Future Med Chem 2(10): 1563–1576.

Borad MA, Jethava DJ, Bhoi MN, Patel CN, Pandya HA, Patel HD (2020) Novel isoniazid-spirooxindole derivatives: design, synthesis, biological evaluation, in silico ADMET prediction and computational studies. J of Mol Struct 1222: 128881.

Chunudom L, Thongsom M, Karim N, Rahman MA, Rana MN, Tangpong J (2020) Tithonia diversifolia aqueous fraction plays a protective role against alloxan-induced diabetic mice via modulating GLUT2 expression. S Afr J Bot 133(1): 118–123.

Cho HI, Hong JM, Choi JW, Choi HS, Hwan Kwak J, Lee DU, Kook Lee S, Lee SM (2015) β-Caryophyllene alleviates D-galactosamine and lipopolysaccharide-induced hepatic injury through suppression of the TLR4 and RAGE signaling pathways. Eur J Pharmacol 764: 613–621.

Daroux M, Prévost G, Maillard-lefebvre H, Gaxatte C (2010) Advanced glycation end-products: implications for diabetic and non-diabetic nephropathies. Diabetes Metab 36(1): 1–10.

Defronzo RA (2009) From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4): 773–795.

Ejelonu OC, Elekofehinti OO, Adanlawo IG, Kundu R (2022) TGR5 potentiates GLP-1 secretion and cause pancreatic islet regeneration in response to Tithonia diversifolia saponin-rich extract in diabetic model mice. Phytomedicine Plus 2(1): 100203.

El Gamal H, Eid AH, Munusamy S (2017) Renoprotective effects of aldose reductase inhibitor epalrestat against high glucose-induced cellular injury. Biomed Res Int 2017: 5903105.

Fatchiyah F, Hardiyanti F, Widodo N (2015) Selective inhibition on RAGE-binding AGEs required by bioactive peptide alpha-S2 case in protein from goat ethawah breed milk: study of biological modeling. Acta Inform Med 23(2): 90–96.

Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, De Fronzo RA (2005) β-cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis. J Clin Endocrinol Metab 90(1): 493–500.

Hsu FY, Lin FJ, Ou HT, Huang SH, Wang CC (2017) Renoprotective effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in diabetic patients with proteinuria. Kidney Blood Press Res 42(2): 358–368.

Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13: 33.

Hussain S, Jamali MC, Habib A, Hussain MS, Akhtar M, Najmi AK (2021) Diabetic kidney disease: an overview of prevalence, risk factor, and biomarkers. Clin Epidemiol Global Health 9: 2–6.

IDF – International Diabetes Federation (2019) IDF Diabetes Atlas, 9th Ed 2019.

Jadoon H, Jadoon S, Jadoon M, Khan S, Mehmood A, Rizwan M, Munir A (2019) In silico target based computational drug repositioning of tolazamide with canagliflozin. Bull Environ Pharmacol Life Sci 8(8): 34–44.

Jia Z, Sun Y, Yang G, Zhang A, Huang S, Heiney KM, Zhang Y (2014) New insights into the PPAR γ agonists for the treatment of diabetic nephropathy. PPAR Res 2014: 818530.

Kajal A, Singh R (2018) An allied approach for in vitro modulation of aldose reductase sorbitol accumulation and advanced glycation end products by flavonoid rich extract of Coriandrum sativum L seeds. Toxicol Rep 5: 800–807.

Kasibhatla B, Wos J, Peters KG (2007) Targeting protein tyrosine phosphatase to enhance insulin action for the potential treatment of diabetes. Curr Opin Investig Drugs 8(10): 805–813.

Kelwade J, Parekh H, Dukle V, Sethi BK (2017) How many oral anti-diabetic drugs before insulin? Indian J Endocrinol Metabol 21(1): 249–250.

Kim YG, Byun J, Yoon D, Jeon JY, Han SJ, Kim DJ, Lee KW, Park RW, Kim HJ (2016) Renal protective effect of DPP-4 inhibitors in type 2 diabetes mellitus patients: a cohort study. J Diabetes Res 2016: 1423191.

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(11): 935–949.

Koepsell H (2004) Polyspecific organic cation transporters: their functions and interactions with drugs. Trend Pharmacol Sci 25(7): 375–381.

Kumar S, Narwal S, Kumar V, Prakash O (2011) α-Glucosidase inhibitors from plants: a natural approach to treat diabetes. Pharmacogn Rev 5(9): 19–29.

Laskowski RA, MacArthur MW, Moss DS, Thornton JM (1993) PROCHECK: a program to check the stereochemical quality of protein structures. J Appl Crystallogr 26(2): 283–291.

Lin HR (2012) Sesquiterpene lactones from Tithonia diversifolia act as peroxisome proliferator-activated receptor agonists. Bioorg Med Chem Lett 22(8): 2954–2958.

Lipinski CA, Lombardo F, Dominy BW, Feeney PJ (2012) Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev 64: 4–17.

May M, Schindler C (2016) Clinically and pharmacologically relevant interactions of antidiabetic drugs. Ther Adv Endocrinol Metab 7(2): 69–83.

Meduru H, Wang YT, Tsai JJP, Chen YC (2016) Finding a potential dipeptidyl peptidase-4 (DPP-4) inhibitor for type-2 diabetes treatment based on molecular docking, pharmacophore generation, and molecular dynamics simulation. Int J Mol Sci 17(6): 920.

Meng XY, Zhang HX, Mezei M, Cui M (2011) Molecular docking: a powerful approach for structure based drug discovery. Curr Comput Aided Drug 7(2): 146–157.

Miura T, Nosaka K, Ishii H, Ishida T (2005) Antidiabetic effect of nitobegiku the herb Tithonia diversifolia in KK-Ay diabetic mice. Biol Pharm Bull 28(11): 2152–2154.

Müller-Krebs S, Kihm LP, Madhusudhan T, Isermann B, Reiser J, Zeier M, and Schwenger V (2012) Human RAGE antibody protects against AGE-mediated podocyte dysfunction. Nephrol Dial Transplant 27(8): 3129–3136.

Naglah AM, Askar AA, Hassan AS, Khatab TK, Al-Omar MA, Bhat MA (2020) Biological evaluation and molecular docking with in silico physicochemical pharmacokinetic and toxicity prediction of pyrazolo[15-a]pyrimidines. Molecules 25(6): 1431.

Ojo A, Ojo AB, Okolie C, Nwakama MAC, Iyobhebhe M, Evbuomwan IO, Nwonuma CO, Maimako RF, Adegboyega AE, Taiwo OA, Alsharif KE, Batiha GES (2021) Deciphering the interactions of bioactive compounds in selected traditional medicinal plants against Alzheimer’s diseases via pharmacophore modeling, auto-QSAR, and molecular docking approaches. Molecules 26(7): 1996.

Pham The H, González-Álvarez I, Bermejo M, Sanjuan VM, Centelles I, Garrigues TM, Cabrera-Pérez MA (2011) In silico prediction of Caco-2 cell permeability by a classification QSAR approach. Mol Inf 30: 376–385.

Pollastri MP (2010) Overview on the rule of five. Curr Protocol Pharmacol 49: 4–12.

Prasad S, Sajja RK, Naik P, and Cucullo L (2014) Diabetes mellitus and blood-brain barrier dysfunction: an overview. J Pharmacovigil 2(2): 125.

Prabhu S, Vijayakumar S, Manogar P, Maniam GP, Govindan N (2017) Homology modeling and molecular docking studies on type II diabetes complications reduced PPAR-ɣ receptor with various ligand molecules. Biomed Pharmacother 92: 528–535.

Pratley RE, Salsali A (2007) Inhibition of DPP-4: A new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin 23(4): 919–931.

Proks P, Reimann F, Green N, Gribble F, Ashcroft F (2002) Sulfonylurea stimulation of insulin secretion. Diabetes 51(3): 368–S376.

Purnomo Y, Soetmadji DW, Sumitro SB, Widodo MA (2014) The comparison of activity dipeptidyl peptidase IV (DPP-IV) inhibitor between Urena lobata and Tithonia diversifolia leaf extract. Diabetes Res Clin Pract 106(1): S121.

Rachmania RA, Supandi, Larasati OA (2015) In silico analysis of diterpenoid lactone compounds of bitter herbs (Andrographis paniculata Nees) on alpha glucosidase receptor as antidiabetic type II agents. Pharmacy 12(2): 210–222.

Rahman N, Muhammad I, Gul-E-Nayab, Khan H, Aschner M, Filosa R, Daglia M (2019) Molecular docking of isolated alkaloids for possible α-glucosidase inhibition. Biomolecules 9(10): 544.

Ramanjaneyulu M, Kumar KA, Kumar MS, Reddy S, Kara D, Mukthala P, Raj R, Madhu C (2013) Target identification and validation for diabetic nephropathy using molecular docking studies. Der Pharma Chem 5(6): 353–363.

Ren JX, Cheng Z, Huang YX, Zhao JF, Guo P, Zou ZM, Xie Y (2017) Identification of novel dual-specificity phosphatase 26 inhibitors by a hybrid virtual screening approach based on pharmacophore and molecular docking. Biomed Pharmacother 89: 376–385.

Rinawati, Suharyanto E, Wijayanti N (2019) The effect of Tithonia diversifolia (Hemsl.) A. Gray leaf decoction on blood glucose levels. BIOTIK 7(1): 41–48.

Rosenwasser RF, Sultan S, Sutton D, Choksi R, Epstein BJ (2013) SGLT-2 inhibitors and their potential in the treatment of diabetes. Diabetes Metab Syndr Obes Targets Ther 6: 453–467.

Rüngeler P, Lyß G, Castro V, Mora G, Pahl H, Merfort I (1998) Study of three sesquiterpene lactones from Tithonia diversifolia on their anti-inflammatory activity using the transcription factor NF-κB and enzymes of the arachidonic acid pathway as targets. Planta Med 64(7): 588–593.

Sanajou D, Haghjo AG, Argani H, Aslani S (2018) AGE-RAGE axis blockade in diabetic nephropathy: current status and future directions. Eur J Pharmacol 833: 158–164.

Saifudin A, Tanaka K, Kadota S, Tezuka Y (2012) Chemical constituents of Blumea balsamifera of Indonesia and their protein tyrosine phosphatase 1b inhibitory activity. Nat Prod Comm 7(7): 815–818.

Shah FH, Salman S, Idrees J, Idrees F, Akbar MY (2020) In silico study of thymohydroquinone interaction with blood–brain barrier disrupting proteins. Future Sci OA 6(10): FSO632.

Singh S, Mohanty A (2018) In silico identification of potential drug compound against peroxisome proliferator-activated receptor-gamma by virtual screening and toxicity studies for the treatment of diabetic nephropathy. J Biomol Struct Dyn 36: 1776–1787.

Soetikno V, Arozal W, Louisa, M, Setiabudi R (2014) New insight into the molecular drug target of diabetic nephropathy. Int J Endocrinol 2014: 968681.

Stanford SM, Aleshin AE, Zhang V, Ardecky RJ, Hedrick MP, Zou J, Ganji SR, Bliss MR, Yamamoto F, Bobkov AA, Kiselar J, Liu Y, Cadwell GW, Khare S, Yu J, Barquilla A, Chung TDY, Mustelin T, Schenk S, Bankston LA, Liddington RC, Pinkerton AB, Bottini N (2017) Diabetes reversal by inhibition of the low-molecular-weight tyrosine phosphatase. Nat Chem Biol 13: 624–632.

Vo TH, Tran N, Nguyen D, Le L (2016) An in silico study on antidiabetic activity of bioactive compounds in Euphorbia thymifolia Linn. SpringerPlus 5(1): 1359.

Wang Y, Wang A, Alkhalidy H, Luo J, Moomaw E, Neilson AP, Liu D (2020) Flavone hispidulin stimulates glucagon-like peptide-1 secretion and ameliorates hyperglycemia in streptozotocin-induced diabetic mice. Mol Nutr 64(6): 1900978.

Wu P, Nielsen TE, Clausen MH (2016) Small-molecule kinase inhibitors: an analysis of FDA-approved drugs. Drug Discov Today 21(1): 5–10.

Yazid F, Salim SO, Rahmadika FD, Rosmalena R, Artanti N, Sundowo A, Prasasty VD (2021) Antidiabetic effects of Tithonia diversifolia and Malus domestica leaf extracts in alloxan-induced Sprague Dawley rats. Sys Rev Pharm 12(1): 1630–1638.

Yue Z, Li L, Fu H, Yin Y, Du B, Wang F, Ding Y, Liu Y, Zhao R, Zhang Z, Yu S (2021) Effect of dapagliflozin on diabetic patients with cardiovascular disease via MAPK signalling pathway. J Cell Mol Med 25: 7500–7512.

Zhao G, Li X, Chen W, Xi Z, Sun L (2012) Three new sesquiterpenes from Tithonia diversifolia and their anti-hyperglycemic activity. Fitoterapia 83(8): 1590–1597.

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