In-silico evaluation of novel quercetin derivatives targeting Plasmodium falciparum dihydrofolate reductase for antimalarial activity

Abstract The global rise in malaria mortality is significantly influenced by the increasing resistance of Plasmodium falciparum to widely used and affordable antimalarial drugs, among other contributing factors, emphasizing the need for novel therapeutic agents. In this study, a series of 84 quercetin-derived ligands were designed and subsequently evaluated in silico as potential inhibitors of the bifunctional enzyme dihydrofolate reductase-thymidylate synthase (DHFR-TS; PDB ID: 1J3K), a validated antimalarial drug target. Virtual screening and molecular docking were performed using AutoDock implemented in PyRx v0.8, followed by molecular dynamics simulations using GROMACS v2024.4. Pharmacokinetic and toxicity profiles were assessed using SwissADME and Protox 3.0. Molecular docking identified 35 designed compounds exhibiting higher predicted binding affinities than the reference drugs cycloguanil (− 6.0 kcal/mol) and pyrimethamine (− 5.2 kcal/mol), with ligand binding energies ranging from − 5.8 to − 9.8 kcal/mol. Among these, ligand b.II exhibited the most favorable predicted binding affinity (− 9.8 kcal/mol) and was selected for further molecular dynamics simulations which indicated stable ligand–protein interactions, with minor differences in dynamic behavior compared to the reference drug, pyrimethamine. ADME analysis of the 35 selected compounds indicated that most of them exhibited favorable pharmacokinetic properties, as reflected by acceptable molecular weight, hydrogen bond donors and acceptors (nHBD, nHBA), lipophilicity (iLogP), and topological polar surface area, along with compliance with drug-likeness parameters such as number of Lipinski rule of five violations and synthetic accessibility, while toxicity studies predicted the ligands to have a low risk of hepatotoxicity, cardiotoxicity, and carcinogenicity. Overall, the findings support the potential of quercetin derivatives, particularly b.II, for further investigation. However, given that these results are derived from computational analyses, experimental validation is necessary to confirm their antimalarial efficacy against multidrug-resistant Plasmodium falciparum .