In silico investigation of tropical natural product for wild-type and quadrupole mutant PfDHFR inhibitors as antimalarial candidates

Abstract

Plasmodium falciparum dihydrofolate reductase (PfDHFR) is an essential enzyme in the development of parasitic DNA and its inhibition often leads to the impediment of parasite growth. Several studies have also shown that a genetic mutation in this enzyme can cause reduced receptor responsiveness and efficacy of antimalarial drugs. Therefore, this study aimed to examine 100 compounds derived from Indonesian medicinal plants as potential antimalarial candidates using a structure-based virtual screening approach. The PASS online was used to screen 100 compounds, and those with Pa values higher than 0.3 were docked with the wild-type (PDB code:1j3i) and quadrupole mutant PfDHFR (PDB code:1j3k). The stability of the chemical complex was then examined using molecular dynamics simulations, followed by an assessment of the pharmacokinetic profile and drug-likeness parameters. The top 5 compounds were then identified with binding energies ranging from -9.7 to -10.0 kcal/mol for the wild-type PfDHFR-TS and from -9.2 to -10.0 kcal/mol for the quadrupole mutant PfDHFR. The results showed that compound C90 exhibited the most stable and impressive score in its pharmacokinetic and drug-likeness assessment.