Molecular Docking Study and Pharmacophore Modelling of Ursolic Acid as an Antimalarial Using Structure-Based Drug Design Method

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 mmol, 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.