MOLECULAR DOCKING STUDY AND PHARMACOPHORE MODELLING OF URSOLIC ACID AS AN ANTIMALARIAL USING STRUCTURE BASED DRUG DESIGN METHOD

Authors

  • FAIZAL HERMANTO Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, West Java 45363, Indonesia https://orcid.org/0000-0001-9054-5167
  • ANAS SUBARNAS Department of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, Universitas Padjadjaran, West Java 45363, Indonesia https://orcid.org/0000-0002-7048-1861
  • AFIFAH BAMBANG SUTJIATMO Department of Pharmacology and Toxicology, Faculty of Pharmacy, Universitas Jenderal Achmad Yani, West Java 40531, Indonesia https://orcid.org/0000-0002-5086-0151
  • AFIAT BERBUDI Department of Biomedical Sciences, Parasitology Division, Faculty of Medicine, Universitas Padjadjaran, West Java 45363, Indonesia https://orcid.org/0000-0001-8809-0810

DOI:

https://doi.org/10.22159/ijap.2023v15i1.46298

Keywords:

Antimalarial, Plasmodium falciparum, Ursolic Acid

Abstract

Objective: To investigate the activity of ursolic acid (UA) as antimalarial on various types and classes of Plasmodium falciparum (Pf) receptors using molecular docking and pharmacophore modeling methods.

Methods: The molecular docking was performed on various classes of the Pf receptors, namely Plasmepsin II (Hydroxylase), Enoyl-Acyl Carrier-protein (Oxidoreductase), Triose-Phosphate (Isomerase), and Lactate Dehydrogenase (Oxidoreductase) using Autodock 4.0.1 software.

Results: three out of four tests (Ursolic Acid on Plasmepsin II, Enoyl-Acyl Carrier, and Lactate Dehydrogenase receptors) indicated a possible effect shown by the lowest free energy binding values obtained, namely -7.76 kcal/mol, -12.15 kcal/mol, and -9.39 kcal/mol, respectively. On Plasmepsin II, Enoyl-Acyl Carrier Protein, Triose-Phosphate Isomerase, and Lactate Dehydrogenase receptors, the UA had lower values of the inhibition constant (2.05 M, 1.25 nm, 1.25 mM, and 130.79 nM, respectively). The UA also shared similarities with the native ligand according to the critical parameters of amino acid residue interaction (GLY216, SER218, LEU131, TYR77, and VAL78 for 1LF3 receptor; ALA217, LYS285, and TYR267 for 1NWH receptor; ASN233 and ALA234, for 1O5X receptor; and PRO246, ILE31, MET30, and PRO 250 for 1U4O receptor). As for the results of pharmacophore modeling, it was found that the functional groups of hydroxyl and carboxylic acid were the most crucial groups to bond with the key amino acid residues of the receptors.

Conclusion: The UA significantly has potential antimalarial activity against several Pf receptors in a competitive manner.

Downloads

Download data is not yet available.

References

WHO Report. World Malaria Report 2017. 2017.

Deress T, Girma M. Plasmodium falciparum and Plasmodium vivax Prevalence in Ethiopia: A Systematic Review and Meta-Analysis. Malar Res and Treat. 2019 Des; 2019:7065064. doi: 10.1155/2019/7065064.

Alven S, Aderibigbe B. Combination therapy strategies for the treatment of malaria. Molecules. 2019 Oct;24(19):3601. doi: 10.3390/molecules24193601.

Innocente AM, Silva GNS, Cruz LN, Moraes MS, Nakabashi M, Sonnet P, et al. Synthesis and antiplasmodial activity of betulinic acid and ursolic acid analogues. Molecules. 2012 Oct;17(10):12003–14. doi: 10.3390/molecules171012003.

Choi WH, Lee IA. The Mechanism of Action of Ursolic Acid as a Potential Anti-Toxoplasmosis Agent, and Its Immunomodulatory Effects. Pathogens. 2019 May;8(2):61. doi: 10.3390/pathogens8020061.

Baliga MS, Shivashankara AR, Venkatesh S, Bhat HP, Palatty PL, Bhandari G, et al. Phytochemicals in the Prevention of Ethanol-Induced Hepatotoxicity: A Revisit. In: Dietary Interventions in Liver Disease: Foods, Nutrients, and Dietary Supplements. Academic Press. 2019. p. 79-89.

Opoku F, Govender PP, Pooe OJ, Simelane MBC. Evaluating iso-mukaadial acetate and ursolic acid acetate as Plasmodium falciparum hypoxanthineguanine-xanthine phosphoribosyltransferase inhibitors. Biomolecules. 2019 Dec;9(12):861. doi: 10.3390/biom9120861.

Perozzo R, Kuo M, Sidhu ABS, Valiyaveettil JT, Bittman R, Jacobs WR, Fidock DA, Sacchettini JC. Structural elucidation of the specificity of the antibacterial agent triclosan for malarial enoyl acyl carrier protein reductase. J Biol Chem. 2002 Apr;277(15):13106-14. doi: 10.1074/jbc.M112000200.

Nunes RR, Da Fonseca AL, Pinto ACDS, Maia EHB, Da Silva AM, Varotti FDP, Taranto AG. Brazilian malaria molecular targets (BraMMT): Selected receptors for virtual high-throughput screening experiments. Mem Inst Oswaldo Cruz. 2019 Feb;114:e180465. doi: 10.1590/0074-02760180465.

Asojo OA, Gulnik S V., Afonina E, Yu B, Ellman JA, Haque TS, Silva AM. Novel uncomplexed and complexed structures of plasmepsin II, an aspartic protease from Plasmodium falciparum. J Mol Biol. 2003 Mar;327(1):173-81. doi: 10.1016/s0022-2836(03)00036-6.

Morris GM, Huey R, Olson AJ. Using AutoDock for ligand-receptor docking. Curr Protoc in Bioinformatics. 2008 Dec;Chapter 8:Unit 8.14. doi: 10.1002/0471250953.bi0814s24.

Bhowmik R, Roy S, Sengupta S, Sharma S. Biocomputational and pharmacological analysis of phytochemicals from zingiber officinale (Ginger), allium sativum (garlic), and murrayakoenigii (curry leaf) in contrast to type 2-diabetes. Int J Appl Pharm. 2021Sep;13(5):280–6. doi : 10.22159/ijap.2021v13i5.42294.

Katelia R, Jauhar MM, Syaifie PH, Ramadhan D, Arda AG, Mardliyati E, Anshori I. in Silico Investigation of Xanthone Derivative Potency in Inhibiting Carbonic Anhydrase Ii (Ca Ii) Using Molecular Docking and Molecular Dynamics (Md) Simulation. Int J Appl Pharm. 2022 Sep;14(5):190–8. doi : 10.22159/ijap.2022v14i5.45388.

Parthasarathy S, Eaazhisai K, Balaram H, Balaram P, Murthy MRN. Structure of Plasmodium falciparum Triose-phosphate Isomerase-2-Phosphoglycerate Complex at 1.1-Å Resolution. J Biol Chem. 2003 Dec;278(52):52461-70. doi: 10.1074/jbc.M308525200.

Langer T, Hoffmann RD. Pharmacophore modelling: Applications in drug discovery. Expert Opinion on Drug Discovery. 2006 Aug;1(3):261-7. doi: 10.1517/17460441.1.3.261.

Caporuscio F, Tafi A. Pharmacophore Modelling: A Forty Year Old Approach and its Modern Synergies. Curr Med Chem. 2011;18(17):2543-53. doi: 10.2174/092986711795933669.

Bissantz C, Kuhn B, Stahl M. A medicinal chemist’s guide to molecular interactions. J Med Chem. 2010 Jul;53(14):5061-84. doi: 10.1021/jm100112j.

Djajadisastra J, Purnama HD, Yanuar A. In silico binding interaction study of mefenamic acid and piroxicam on human albumin. Int J Appl Pharm. 2017;9. doi : 10.22159/ijap.2017.v9s1.56_62

Niu Y, Liu R, Guan C, Zhang Y, Chen Z, Hoerer S, Nar H, Chen L. Structural basis of inhibition of the human SGLT2–MAP17 glucose transporter. Nature. 2022 Jan;601(7892):280-284. doi: 10.1038/s41586-021-04212-9.

Cournia Z, Allen B, Sherman W. Relative Binding Free Energy Calculations in Drug Discovery: Recent Advances and Practical Considerations. Journal of Chemical Information and Modeling. 2017 Dec;57(12):2911-2937. doi: 10.1021/acs.jcim.7b00564.

Luo H, Fokoue-Nkoutche A, Singh N, Yang L, Hu J, Zhang P. Molecular Docking for Prediction and Interpretation of Adverse Drug Reactions. Comb Chem High Throughput Screen. 2018;21(5):314-322. doi: 10.2174/1386207321666180524110013 .

Muchtaridi M, Syahidah HN, Subarnas A, Yusuf M, Bryant SD, Langer T. Molecular docking and 3D-pharmacophore modeling to study the interactions of chalcone derivatives with estrogen receptor alpha. Pharmaceuticals. 2017 Oct;10(4):81. doi: 10.3390/ph10040081.

Wang J, Zhao J, Yan Y, Liu D, Wang C, Wang H. Inhibition of glycosidase by ursolic acid: in vitro, in vivo and in silico study. J Sci Food Agric. 2020 Feb;100(3):986-994. doi: 10.1002/jsfa.10098. Epub 2019 Dec 17.

Zahran EM, Abdelmohsen UR, Ayoub AT, Salem MA, Khalil HE, Desoukey SY, et al. Metabolic profiling, histopathological anti-ulcer study, molecular docking and molecular dynamics of ursolic acid isolated from Ocimum forskolei Benth. (family Lamiaceae). South African J Bot. 2020;131:311-310. doi : 10.1016/j.sajb.2020.03.004.

Han HS, Kang G, Kim JS, Choi BH, Koo SH. Regulation of glucose metabolism from a liver-centric perspective. Vol. 48, Experimental and Molecular Medicine. 2016 Mar;48(3):e218. doi: 10.1038/emm.2015.122.

Ravichandran S, Singh N, Donnelly D, Migliore M, Johnson P, Fishwick C, Luke BT, Maudsley S, Fugmann SD, Moaddel R. Pharmacophore model of the quercetin binding site of the SIRT6 protein. J Mol Graph Model. 2014 Apr;49:38-46. doi: 10.1016/j.jmgm.2014.01.004.

Seeliger D, De Groot BL. Ligand docking and binding site analysis with PyMOL and Autodock/Vina. J Comput Aided Mol Des. 2010 May;24(5):417-22. doi: 10.1007/s10822-010-9352-6.

Shityakov S, Förster C. In silico structure-based screening of versatile P-glycoprotein inhibitors using polynomial empirical scoring functions. Adv Appl Bioinforma Chem. 2014 Mar;7:1-9. doi: 10.2147/AABC.S56046

Morozov A V., Kortemme T. Potential Functions for Hydrogen Bonds in Protein Structure Prediction and Design. Vol. 72, Adv Protein Chem. 2005;72:1-38. doi: 10.1016/S0065-3233(05)72001-5.

Matta CF, Hernández-Trujillo J, Tang TH, Bader RFW. Hydrogen - Hydrogen bonding: A stabilizing interaction in molecules and crystals. J Chem. 2003 May 9;9(9):1940-51. doi: 10.1002/chem.200204626.

Kumar S, Khatik GL, Mittal A. In silico Molecular Docking Study to Search New SGLT2 Inhibitor based on Dioxabicyclo[3.2.1] Octane Scaffold. Curr Comput Aided Drug Des. 2020;16(2):145-154. doi: 10.2174/1573409914666181019165821.

Published

21-10-2022

How to Cite

HERMANTO, F., SUBARNAS, A., BAMBANG SUTJIATMO, A., & BERBUDI, A. (2022). MOLECULAR DOCKING STUDY AND PHARMACOPHORE MODELLING OF URSOLIC ACID AS AN ANTIMALARIAL USING STRUCTURE BASED DRUG DESIGN METHOD. International Journal of Applied Pharmaceutics, 15(1). https://doi.org/10.22159/ijap.2023v15i1.46298

Issue

Section

Original Article(s)

Most read articles by the same author(s)