Page 116 - ITPS-7-1

INNOSC Theranostics

and Pharmacological Sciences

ORIGINAL RESEARCH ARTICLE
Drug repurposing approach for identifying

Pfmrk inhibitors as potential antimalarial
agents: An in silico analysis

Abhishek Sahu*, Tanuj Handa, and Debanjan Kundu

School of Biochemical Engineering, Indian Institute of Technology (Banaras Hindu University),
Varanasi, Uttar Pradesh, India

Abstract

Malaria represents a major global health concern, primarily due to the emergence
of resistance against most currently available antimalarial drugs. This pressing issue
necessitates the discovery of novel antimalarial agents to combat the escalating
resistance. A cyclin-dependent kinase (CDK)-like protein, Pfmrk, found in Plasmodium
falciparum, plays a crucial role in regulating cell proliferation and exhibits a 36.28%
sequence homology with its human counterpart hCDK7. Pfmrk forms a complex with
plasmodial cyclin (Pfcyc-1) and stimulates kinase activity. Pfcyc-1 from P. falciparum,
with the highest sequence homology to human cyclin (cyclin H), binds and activates
Pfmrk in a cyclin-dependent manner. This discovery provides the first indication that
cyclin subunits may regulate both human and plasmodial CDKs in a similar fashion.
In this study, we conducted molecular docking and simulation analysis to investigate
the interaction between Pfmrk and a selection of the FDA-approved drugs retrieved
*Corresponding author: from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex,
Abhishek Sahu
(abhisheksahu.bce20@itbhu.ac.in) Alvesco, and Orap – were screened based on their binding energies, with the best-
docked scores ranging between −8 kcal/mol and −12 kcal/mol. Further, evaluation
Citation: Sahu A, Handa T, Kundu through molecular dynamics simulations for 100 nanoseconds revealed that
D, 2024, Drug repurposing approach
for identifying Pfmrk inhibitors Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed
as potential antimalarial agents: by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the
An in silico analysis. INNOSC amino acid residues located in the active site of Pfmrk. The results of the in silico
Theranostics and Pharmacological
Sciences, 7(1): 1313. investigation indicate that Lurasidone and Donovex exhibit antimalarial potential
https://doi.org/10.36922/itps.1313 and could serve as promising Pfmrk inhibitors. Further, development of new drugs
Received: June 15, 2023 based on these findings warrants subsequent in vitro studies.
Accepted: September 6, 2023
Keywords: Pfmrk; Plasmodium falciparum; Molecular docking; Drug discovery; Molecular
Published Online: November 2, 2023
dynamics
Copyright: © 2023 Author(s).
This is an Open-Access article
distributed under the terms of the
Creative Commons Attribution
License, permitting distribution, 1. Introduction
and reproduction in any medium,
provided the original work is The term “Malaria” originates from the Italian word “mal-aria,” signifying its
properly cited. association with the noxious air prevalent in regions characterized by stagnant, swampy
Publisher’s Note: AccScience environments. Malaria is primarily transmitted through the bites of female Anopheles
Publishing remains neutral with mosquitoes carrying the infectious Plasmodium species, which belong to the eukaryotic
regard to jurisdictional claims in [1]
published maps and institutional unicellular organisms, classified under the Apicomplexa phylum . Several Plasmodium
affiliations. species can infect humans, including Plasmodium falciparum, Plasmodium vivax,

Volume 7 Issue 1 (2024) 1 https://doi.org/10.36922/itps.1313