Polyether ionophores as potential antimalarial

J. Pharm. Pharmacogn. Res., vol. 10, no. 6, pp. 1139-1148, November-December 2022.

DOI: https://doi.org/10.56499/jppres22.1478_10.6.1139

Original Article

Potential of polyether ionophore compounds as antimalarials through inhibition on Plasmodium falciparum glutathione S-transferase by molecular docking studies

[Potencial de los compuestos ionóforos de poliéter como antimaláricos mediante la inhibición de glutatión S-transferasa de Plasmodium falciparum a través de estudios de acoplamiento molecular]

Alfian Wika Cahyono1,2, Icha Farihah Deniyati Faratisha1, Nabila Erina Erwan1,3, Rivo Yudhinata Brian Nugraha1,4, Ajeng Maharani Putri1,3, Loeki Enggar Fitri1,4*

1Malaria Research Group, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia.

2Doctoral Program in Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia.

3Master Program in Biomedical Science, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia.

4Department of Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, East Java, 65145, Indonesia.

*E-mail: lukief@ub.ac.id


Context: Malaria is still a serious global health problem due to the development of drug resistance. It is necessary to find new drugs with renewable mechanisms that are effective in killing parasites. Our previous research has analyzed more than one compound of polyether ionophore group in ethyl acetate Streptomyces hygroscopicus subsp. hygroscopicus extract. Polyether ionophore is known to have a similar mechanism of action to chloroquine which is potent in inhibiting Plasmodium falciparum glutathione S-transferase (PfGST).

Aims: To evaluate the potential effect of polyether ionophore toward PfGST as a target protein through molecular docking.

Methods: PfGST was obtained from Protein Data Bank. Test ligands (polyether ionophore) and control ligands (chloroquine) were obtained from PubChem. Pharmacokinetic analysis was done using SwissADME, molecular docking using PyRx 0.9, visualization using LigPlot and PyMOL, and molecular dynamics using YASARA for the best ligand activity.

Results: Lenoremycin had the highest binding affinity to PfGST (-8.53 kcal/mol) among other polyether ionophores, and nigericin had the best residue bonding with hydrophobic and hydrogen with a binding affinity of -8.25 kcal/mol compared to chloroquine complex in molecular docking and molecular dynamic simulation.

Conclusions: Polyether ionophore could serve as an antimalarial agent better than chloroquine, with nigericin as the best compound candidate in inhibiting PfGST compared to other polyether ionophores.

Keywords: malaria; molecular docking; PfGST; polyether ionophore; Streptomyces hygroscopicus.



Contexto: La malaria sigue siendo un grave problema sanitario mundial debido al desarrollo de resistencia a los fármacos. Es necesario encontrar nuevos fármacos con mecanismos renovables que sean eficaces para matar a los parásitos. Nuestra investigación anterior ha analizado más de un compuesto del grupo ionóforo poliéter en el extracto de acetato de etilo de Streptomyces hygroscopicus subsp. hygroscopicus. Se sabe que el poliéter ionóforo tiene un mecanismo de acción similar al de la cloroquina, que es potente inhibidor de la gutatión S-transferasa de Plasmodiun falciparum (PfGST).

Objetivos: Evaluar el efecto potencial del poliéter ionóforo hacia la PfGST como proteína diana a través del acoplamiento molecular.

Métodos: PfGST se obtuvo del Banco de Datos de Proteínas. Los ligandos de prueba (poliéter ionóforo) y los ligandos de control (cloroquina) se obtuvieron de PubChem. El análisis farmacocinético se realizó con SwissADME, el docking molecular con PyRx 0.9, la visualización con LigPlot y PyMOL, y la dinámica molecular con YASARA para la mejor actividad del ligando.

Resultados: La lenoremycina tuvo la mayor afinidad de unión a PfGST (-8,53 kcal/mol) entre otros poliéteres ionóforos, y la nigericina tuvo la mejor unión de residuos con hidrófobos e hidrógenos con una afinidad de unión de -8,25 kcal/mol en comparación con el complejo de cloroquina en el docking molecular y la simulación dinámica molecular.

Conclusiones: El ionóforo poliéter podría servir como agente antimalárico mejor que la cloroquina, siendo la nigericina el mejor candidato para inhibir el PfGST en comparación con otros ionóforos poliéter.

Palabras Clave: acoplamiento molecular; ionóforo poliéter; malaria; PfGST; Streptomyces hygroscopicus.

Citation Format: Cahyono AW, Faratisha IFD, Erwan NE, Nugraha RYB, Putri AM, Fitri LE (2022) Potential of polyether ionophore compounds as antimalarials through inhibition on Plasmodium falciparum glutathione S-transferase by molecular docking studies. J Pharm Pharmacogn Res 10(6): 1139–1148. https://doi.org/10.56499/jppres22.1478_10.6.1139

Abkar AH, Djati MS, Widodo W (2021) In silico study to predict the potential of beta asarone, methyl piperonylketone, coumaric acid in Piper crocatum as anticancer agents. J Exp Life Sci 11: 89–99. https://doi.org/10.21776/ub.jels.2021.011.03.04

Adovelande J, Schrével J (1996) Carboxylic ionophores in malaria chemotherapy: The effects of monensin and nigericin on Plasmodium falciparum in vitro and Plasmodium vinckei petteri in vivo. Life Sci 59: 309-315. https://doi.org/10.1016/s0024-3205(96)00514-0

Fitri LE, Alkarimah A, Cahyono AW, Lady WN, Endharti AT, Nugraha RYB (2019) Effect of metabolite extract of Streptomyces hygroscopicus subsp. hygroscopicus on Plasmodium falciparum 3D7 in vitro. Iran J Parasitol 14: 444–452.

Gumila C, Ancelin ML, Delort AM, Jeminet G, Vial HJ (1997) Characterization of the potent in vitro and in vivo antimalarial activities of ionophore compounds. Antimicrob Agents Chemother 41: 523–529. https://doi.org/10.1128/AAC.41.3.523

Hartuti ED, Inaoka DK, Komatsuya K, Miyazaki Y, Miller RJ, Xinying W, Sadikin M, Prabandari EE, Waluyo D, Kuroda M, Amalia E, Matsuo Y, Nugroho NB, Saimoto H, Pramisandi A, Watanabe YI, Mori M, Shiomi K, Balogun EO, Shiba T, Harada S, Nozaki T, Kita K (2018) Biochemical studies of membrane bound Plasmodium falciparum mitochondrial L-malate:quinone oxidoreductase, a potential drug target. Biochim Biophys Acta Bioenerg 1859: 191–200. https://doi.org/10.1016/j.bbabio.2017.12.004

Harwaldt P, Rahlfs S, Becker K (2002) Glutathione S-transferase of the malarial parasite Plasmodium falciparum: Characterization of a potential drug target. Biol Chem 383: 821–830. https://doi.org/10.1515/BC.2002.086

Hiller N, Fritz-Wolf K, Deponte M, Wende W, Zimmermann H, Becker K (2006) Plasmodium falciparum glutathione S-transferase–structural and mechanistic studies on ligand binding and enzyme inhibition. Protein Sci 15: 281–289. https://doi.org/10.1110/ps.051891106

Huczyński A (2012) Polyether ionophores—promising bioactive molecules for cancer therapy. Bioorg Med Chem Lett 22: 7002–7010. https://doi.org/10.1016/j.bmcl.2012.09.046

Kevin II DA, Meujo DA, Hamann MT (2009) Polyether ionophores: Broad-spectrum and promising biologically active molecules for the control of drug-resistant bacteria and parasites. Expert Opin Drug Discov 4: 109–146. https://doi.org/10.1517/17460440802661443

Liebau E, Bergmann B, Campbell AM, Teesdale-Spittle P, Brophy PM, Lüersen K, Walter RD (2002) The glutathione S-transferase from Plasmodium falciparum. Mol Biochem Parasitol 124: 85–90. https://doi.org/10.1016/s0166-6851(02)00160-3

Na M, Meujo DAF, Kevin D, Hamann MT, Anderson M, Hill RT (2008) A new antimalarial polyether from a marine Streptomyces sp. H668. Tetrahedron Lett 49: 6282–6285. https://doi.org/10.1016/j.tetlet.2008.08.052

Novilla MN, McClary D, Laudert SB (2017) Chapter 29 – Ionophores, in: Gupta, R.C. (Ed.), Reproductive and Developmental Toxicology (2th Edition). Academic Press, pp. 503–518. https://doi.org/10.1016/B978-0-12-804239-7.00029-9

Otoguro K, Kohana A, Manabe C, Ishiyama A, Ui H, Shiomi K, Yamada H, Omura S (2001) Potent antimalarial activities of polyether antibiotic, X-206. J Antibiot (Tokyo) 54: 658–663. https://doi.org/10.7164/antibiotics.54.658

Perbandt M, Eberle R, Fischer-Riepe L, Cang H, Liebau E, Betzel C (2015) High resolution structures of Plasmodium falciparum GST complexes provide novel insights into the dimer–tetramer transition and a novel ligand-binding site. J Struct Biol 191: 365–375. https://doi.org/10.1016/j.jsb.2015.06.008

PubChem (2008) Sodium carriomycin. Available: https://pubchem.ncbi.nlm.nih.gov/compound/23698022 [Accessed 24 August 2021].

PubChem (2007) Septamycin sodium salt. Available: https://pubchem.ncbi.nlm.nih.gov/compound/23693333 [Accessed 24 August 2021].

PubChem (2006) Lenoremycin. Available: https://pubchem.ncbi.nlm.nih.gov/compound/6441669 [Accessed 24 August 2021].

PubChem (2005a) Nigericin. Available: https://pubchem.ncbi.nlm.nih.gov/compound/34230 [Accessed 24 August 2021].

PubChem (2005b) Dianemycin. Available: https://pubchem.ncbi.nlm.nih.gov/compound/5475287 [Accessed 24 August 2021].

PubChem (2005c) Etheromycin. Available: https://pubchem.ncbi.nlm.nih.gov/compound/3042207 [Accessed 24 August 2021].

Rajendran V, Rohra S, Raza M, Hasan GM, Dutt S, Ghosh PC (2015) Stearylamine liposomal delivery of monensin in combination with free artemisinin eliminates blood stages of Plasmodium falciparum in culture and P. berghei infection in murine malaria. Antimicrob Agents Chemother 60: 1304–1318. https://doi.org/10.1128/AAC.01796-15

Raphemot R, Posfai D, Derbyshire ER (2016) Current therapies and future possibilities for drug development against liver-stage malaria. J Clin Invest 126: 2013–2020. https://doi.org/10.1172/JCI82981

Rivo YB, Alkarimah A, Ramadhani NN, Cahyono AW, Laksmi DA, Winarsih S, Fitri LE (2013) Metabolite extract of Streptomyces hygroscopicus Hygroscopicus inhibit the growth of Plasmodium berghei through inhibition of ubiquitin-proteasome system. Trop Biomed 30: 291–300.

Rutkowski J, Brzezinski B (2013) Structures and properties of naturally occurring polyether antibiotics. Biomed Res Int 2013: 162513. https://doi.org/10.1155/2013/162513

World Health Organization (2020) World malaria report: 20 years of global progress and challenges. Available: https://www.who.int/publications/i/item/9789240015791 [Accessed 25 August 2021].

© 2022 Journal of Pharmacy & Pharmacognosy Research (JPPRes)