New inhibitor quadrupole mutant PfDHFR as antimalaria candidate: Structure-based pharmacophore, molecular docking, ADMET, molecular dynamic, and chemical quantum study

Genetic mutations in the dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) enzyme of the malaria parasite Plasmodium falciparum have been shown to reduce the effectiveness of several approved antimalarial drugs. This phenomenon has become a new challenge to the malaria control and treatment sector. As a result, the goal of this study is to identify the best compound with the potential to be an antimalarial agent by employing a good model pharmacophore generated by mutated PfDHFR as a receptor. Using a computational chemistry method, a structurebased pharmacophore was utilized to analyze 165,878 compounds from the zinc database. Subsequently, these compounds were further examined by molecular docking. Furthermore, the ADMET properties, including absorption, distribution, metabolism, excretion, and toxicity, of these drug-candidates have been assessed. Furthermore, molecular dynamic simulations were employed to investigate the stability of the compound-receptor complex, while DFT investigations were utilized to examine the electronic characteristics of these compounds. Overall findings indicated that the substance C431 (ZINC257280996) may be a potent PfDHFR-TS inhibitor due to its favorable binding energy of -42.26 kJ/mol, molecular dynamics simulations' indication of its stability, and its advantageous pharmacokinetic characteristics along with its non-toxic nature. The findings suggested that compound C431 could be a promising antimalarial candidate. Furthermore, this research provides guidance for improving the structure of compound C431 for future synthesis and verifies its antimalarial efficacy in vitro.