Pharmacophore Screening and Molecular Docking of Andrographolide and Its Derivatives on Plasmepsin as Antimalarial Drug

Sandra Megantara

Abstract

The study was conducted to find out andrographolide and its derivatives which could interact with plasmepsin, an aspartic protease enzyme that usually used as target for antimalaria. The study began with pharmacophore modeling using LigandScout software. Pharmacophores were searched for plasmepsin I, II, and IV, with pdb codes were 3QS1, 1SME, and 1LS5 respectively. Pharmacophores were generated using structure-based and ligand-based pharmacophore methods and retrospective validation was used to validate them. Pharmacophore screening was carried out for andrographolide and its derivatives, then for the hit compounds, continued by molecular docking using AutoDock Vina module in LigandScout software. Pharmacophores for plasmepsin I, II, and IV consist of hydrogen bond donors, hydrogen bond acceptors and hydrophobic interactions, with the best validated AUC values for each model were 0.73, 1.00, and 1.00 respectively. Andrographolide derivatives (AND10 and AND15) had high fit scores for plasmepsin I, II, and IV pharmacophore. The results of molecular docking showed that andrographolide and its derivatives (AND10 and AND15) interacted well with the plasmepsin by binding to important aspartic amino acid residues in the active site. From the binding affinity, AND15 was the best compound interacted with plasmepsin I, II, and IV with ∆G values were 1, 2, and 3 kcal/mol respectively. Andrographolide derivative (AND15) was the best compound interacted with plasmepsin, so it was potential to be developed into new antimalarial drug.

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References

WHO (2018) World Malaria Report. World Health Organization.

WHO (2017) Annex 6A - Reported malaria cases and deaths. World Malaria Report 2017. Geneva, Switzerland: WHO, 222-225.

Singh Sidhu AB, Verdier-Pinard D, Fidock DA (2002) Chloroquine resistance in Plasmodium falciparum malaria parasites conferred by pfcrt mutations. Sci., 298(5591):210–3.

Aweeka FT, German PI (2008) Clinical pharmacology of artemisinin-based combination therapies. Clin Pharmacokinet., 47(2):91–102.

WHO. Guidelines for the Treatment of Malaria. World Health Organization. 2015.

Francis SE, Sullivan Jr. DJ, Goldberg DE (1997) Hemoglobin metabolism in the malaria parasite Plasmodium falciparum. Annu Rev Microbiol., 51:97–123.

Coombs GH, Goldberg DE, Klemba M, Berry C, Kay J, Mottram JC (2001) Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets. Trends Parasitol., 17(11):532–7.

Misra P, Pal NL, Guru PY, Katiyar JC, Tandon JS (1991) Antimalarial activity of traditional plants against erythrocytic stages of plasmodium berghei. Pharm Biol., 29(1):19–23.

Najib NARN, Furuta T, Kojima S, Takane K, Ali Mohd M (1999) Antimalarial activity of extracts of Malaysian medicinal plants. J Ethnopharmacol., 64(3):249–54.

Zein U, Fitri LE, Saragih A (2013) Comparative study of antimalarial effect of sambiloto (Andrographis paniculata) extract, chloroquine and artemisinin and their combination against plasmodium falciparum in-vitro. Acta Med Indones., 45(1):38–43.

Chang RS, Ding L, Gai-Qing C, Qi-Choa P, Ze-Lin Z, Smith KM (1991) Dehydroandrographolide Succinic Acid Monoester as an Inhibitor against the Human Immunodeficiency Virus. Proc Soc Exp Biol Med., 197(1):59–66.

Aromdee C (2014) Andrographolide: Progression in its modifications and applications-a patent review (2012-2014). Expert Opin Ther Pat., 24(10):1129–38.

Uttekar MM, Das T, Pawar RS, Bhandari B, Menon V, Nutan, et al (2012) Anti-HIV activity of semisynthetic derivatives of andrographolide and computational study of HIV-1 gp120 protein binding. Eur J Med Chem., 56:368–74.

Wang Z, Yu P, Zhang G, Xu L, Wang D, Wang L, et al (2010) Design, synthesis and antibacterial activity of novel andrographolide derivatives. Bioorg Med Chem., 18(12):4269–74.

Megantara S, Halimah H, Putrianty A, Tjahjono DH, Kartasasmita RE, Iwo MI, et al (2018) Microwave-assisted synthesis of hydroxybenzylidene-andrographolides and its inhibitory activity against HIV-1 protease. J Appl Pharm Sci., 8(3):009–13.

Zhou B, Zhang D, Wu X (2013) Biological Activities and Corresponding SARs of Andrographolide and Its Derivatives. Mini-Reviews Med Chem., 13(2):298–309.

Wolber G, Langer T (2005) LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model., 45(1):160–9.

Halgren TA (1999) MMFF VI. MMFF94s option for energy minimization studies. J Comput Chem., 20(7):720–9.

Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem., 31(2):455–61.

Niu MM, Qin JY, Tian CP, Yan XF, Dong FG, Cheng ZQ, et al (2014) Tubulin inhibitors: Pharmacophore modeling, virtual screening and molecular docking. Acta Pharmacol Sin., 35(7):967–79.

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