Drug repurposing approach for identifying Pfmrk inhibitors as potential antimalarial agents: An in silico analysis

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 from the ZINC15 database. The top five drugs – Lurasidone, Vorapaxar, Donovex, 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 through molecular dynamics simulations for 100 nanoseconds revealed that Lurasidone exhibited the highest binding affinity (−105.90 ± 57.72 kJ/mol) followed by Donovex (−92.877 ± 17.872 kJ/mol). They exhibited stable interactions with the amino acid residues located in the active site of Pfmrk. The results of the in silico investigation indicate that Lurasidone and Donovex exhibit antimalarial potential and could serve as promising Pfmrk inhibitors. Further, development of new drugs based on these findings warrants subsequent in vitro studies.