Investigation on Anti‐plasmodial Agents Against wild‐type PfDHFR Through In Silico Computational Tools

Abstract Malaria is the most severe and common parasitic infection, with P. falciparum responsible for the majority of cases and deaths each year. As anti‐malarial drug resistance continues to increase, novel compounds with anti‐ P. falciparum activity must be identified. In search of a new molecule to cure the resistant malarial parasite, a total of 1,70,269 ligands from the Asinex BioDesign library 2021.2 were virtually screened using AutoDock Vina against wild‐type P. falciparum dihydrofolate reductase‐thymidylate synthase ( Pf DHFR‐TS). The computational molecular modeling investigations indicated the discovery of seventeen new compounds ( 2 ‐ 18 ) with higher binding energy compared to the Pf DHFR‐TS inhibitor, pyrimethamine ( 1 ). Furthermore, the study employing drug‐likeness criteria and their ADMET profile suggested that these hits were the most promising drug candidates due to higher absorption and druggability. Furthermore, GROMACS 2023.4 was used to perform the molecular dynamics simulations on the foremost compound ( 2 ) having sufficient stability, leading to a key step towards the search of novel Pf DHFR‐TS inhibitors against malaria.