In-Silico Evaluation of Novel Quercetin Derivatives as Antimalarial Agents Targeting Plasmodium falciparum Dihydrofolate Reductase: Molecular Docking, Molecular Dynamics Simulations, and Pharmacokinetic and Toxicity Predictions

The global rise in malaria mortality is largely driven by the increasing resistance of Plasmodium falciparum to widely used and affordable antimalarial drugs, emphasizing the urgent need for novel therapeutic agents. In this study, thirty-five ligands were computationally evaluated 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. ADME analysis revealed favorable pharmacokinetic properties for most compounds, while toxicity predictions classified the majority into Classes IV and V, indicating low acute toxicity, with all promising ligands predicted to be non-hepatotoxic, non-cardiotoxic, and non-carcinogenic. Among the evaluated compounds, six ligands (b.II, b.III, b.VIII, I.b, II.b, and VII.b) exhibited higher binding affinities toward DHFR-TS than the reference drugs cycloguanil and pyrimethamine. These ligands formed strong hydrogen bonding and van der Waals interactions with key active-site residues, including SER A:167, LEU A:40, ILE A:14, LEU A:164, ASN A:33, THR A:36, GLU A:25, and CYS A:27, contributing to enhanced binding stability. Notably, ligand b.II demonstrated the strongest binding affinity and sustained stability, identifying it as a promising lead candidate for further experimental validation against multidrug-resistant Plasmodium falciparum.