QSAR and Molecular Docking of Pyrimidine Derivatives Against Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (PfDHFR-TS)

Abstract

New pyrimidine compounds were developed using quantitative structure-activity relationship (QSAR) analysis and molecular docking. The aim of the research was to find the best QSAR equation and to investigate the interaction of the new compound with the target protein of dihydrofolate reductase thymidylate synthase of P. falciparum by molecular docking. Each compound was optimized using AM1 computational methods. In QSAR analysis, statistical calculations involving multi-linear regression (MLR) were performed. The results of QSAR analysis yielded the best equation model, namely Log pMIC = 10.441-16.769 (qC7)-15.880 (qC9) + 5.809 (qC12) + 10.612 (qC13) + 114.506 (LUMO). The addition of electron donating groups such as hydroxyl, amino, N,N-dimethyl amine and halogen also enhanced the antimalarial activity. The molecular docking results showed that the new design of pyrimidine compounds is able to interact with important amino acid residues on the target protein via hydrogen bonds. The presence of pyrrolidine on the C3 pyrimidine ring contributed to the interaction with key amino acid residues via hydrophobic interactions.