Drug repurposing approach for potential Pfmrk inhibitors as antimalarial agents: anIn-silicoanalysis

Abstract

AbstractMalaria is a major global health issue due to the emergence of resistance to most of the available antimalarial drugs. There is an urgent need to discover new antimalarials to tackle the resistance issue. A CDK-like protein, Pfmrk fromPlasmodium falciparum, plays a crucial role in regulating cell proliferation and shares 36.28% homology with humans CDK (hCDK7). Pfmrk complex with Pfcyc-1 and stimulates kinase activity. Also, Pfcyc-1 from P. falciparum, which has the highest sequence homology with human cyclin (Cyclin H), binds to and activates Pfmrk in a cyclin-dependent way. This is the first indication that cyclin subunits regulate human and plasmodial CDKs in a similar manner. In this study, molecular docking analysis of Pfmrk against the selected FDA-approved drugs acquired from the ZINC15 database. The top five drugs, Lurasidone, Vorapaxar, Donovex, Alvesco, and Orap, were screened based on binding energies of best-docked scores ranging between -8 kcal/mol and -12 kcal/mol. Based on Molecular dynamics simulations for 100ns, Lurasidone showed the highest binding affinity (-105.90 ± 57.72 kJ/mol), followed by Donovex (-92.877 ± 17.872 kJ/mol) and exhibited stable interactions with the amino acid residues present in the active site of Pfmrk. The outcomes ofin silicoinvestigation putatively suggested that Lurasidone and Donovex exhibit antimalarial potency and could be translated as potential Pfmrk inhibitors and developing new drugs based on furtherin-vitrostudies.Graphical AbstractHighlightsWe investigated the potential FDA-approved drugs for repurposing against the modelled protein Pfmrk.Alvesco, Donovex, Lurasidone, Orap, and Vorapaxar are potential FDA-approved drugs firmly binding with Pfmrk.Molecular docking and simulation studies show that Donovex and Lurasidone are potential inhibitors of the modelled Pfmrk protein.Donovex and Lurasidone are potential drugs that act as kinase inhibitors by binding to the ATP -binding site of the enzyme Pfmrk.