Molecular Docking Study Of 1‑(Pyridin-4-Yl)Pyrrolidine-2-One Derivate Against Prolyl-tRNA Synthetase In Plasmodium Falciparum

Yuniarta, Tegar Achsendo and Wawo, Jesica Ersty and Kesuma, Dini (2022) Molecular Docking Study Of 1‑(Pyridin-4-Yl)Pyrrolidine-2-One Derivate Against Prolyl-tRNA Synthetase In Plasmodium Falciparum. Pharmacoscript, 5 (2). pp. 157-171. ISSN 2685-1121 (online); 2622-4941 (print)

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Abstract

Prolyl-tRNA synthetase is one of the novel targets to develop antimalarial drug candidate. Several class of inhibitors have been identified for the enzyme, one of which is pyridine-pyrrolidinone derivative. It is recently known that 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide possess potent antimalarial activity, possibly via prolyl-tRNA synthetase inhibition. This compound possesses two enantiomeric form which yielded antimalarial bioactivity in different magnitude. It is argued that this compound occupies ATP binding site. However, 3D structure of ligand-protein complex has yet to be elucidated. This study aimed to predict binding mode and affinity of two enantiomers of 4‐[3‐cyano‐3‐(1‐methylcyclopropyl)‐2‐oxopyrrolidin‐1‐yl]‐N‐{[3‐fluoro‐5‐(1‐methyl‐1H‐pyrazol‐4‐yl)phenyl]methyl}‐6‐methylpyridine‐2‐carboxamide using molecular docking approach with EasyDockVina 2.2. The results showed that S enantiomer possess better ligand affinity (-0.81±3.98) compared to R enantiomer (1.74±2.71). The result was in line with in vitro antimalarial assay, which stated the potency of S enantiomer more than R enantiomer. In addition, it is argued that residue GLN475 and THR478 plays important role in ligand-enzyme interaction. Further studies are needed to verify the result with more robust in silico method and enzymatic bioassay.

Item Type:	Article
Uncontrolled Keywords:	antimalaria, molecular docking, pyridine-pyrolidine, prolyl-tRNA synthetase, stereochemistry
Subjects:	Q Science > QD Chemistry
Divisions:	Faculty of Pharmacy > Department of Pharmacy
Depositing User:	TEGAR ACHSENDO YUNIARTA
Date Deposited:	07 Sep 2022 05:23
Last Modified:	23 Sep 2022 03:59
URI:	http://repository.ubaya.ac.id/id/eprint/42477

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