MOLECULAR DOCKING STUDY OF 1‑(PYRIDIN-4-YL)PYRROLIDINE-2-ONE DERIVATE AGAINST PROLYL-tRNA SYNTHETASE IN PLASMODIUM FALCIPARUM

Authors

  • Tegar Achsendo Yuniarta Faculty of Pharmacy, University of Surabaya
  • Jesica Ersty Wawo Faculty of Pharmacy, University of Surabaya
  • Dini Kesuma Faculty of Pharmacy, University of Surabaya

DOI:

https://doi.org/10.36423/pharmacoscript.v5i2.1003

Keywords:

antimalaria, molecular docking, pyridine-pyrolidine, prolyl-tRNA synthetase, stereochemistry

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.

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Published

2022-08-31