Abstract

Malaria is a parasitic disease mainly caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale and rarely by animal plasmodium such as Plasmodium knowlesi. Despite the worldwide endorsement of eradicating malaria, the mortality and morbidity of malaria is still high, especially in children of resource-poor regions of the world. In the current study, a series of 2-pyridyl pyrimidine derivatives with P. falciparum methionine aminopeptidase 1b (MA1b) inhibitory activity were subjected to quantitative structure, relationship activities, molecular docking, and molecular dynamics simulation to identify the ideal physicochemical characteristics and the drug–receptor interactions of potential antimalarial compounds. The structures were built using HyperChem. A docking study was performed using AutoDock. The obtained quantitative structure activity relationships model has showed that the descriptors MLOGP, E2p, Mor24u, PW2, and H8m mainly affect the antimalarial activity of the series of ligands. The residues His 277, Fe 370, Asp 240, Trp 320, and Tyr 260 of MA1b play a very important role in the drug–enzyme interaction by creating hydrogen bond, π-cation, and π-π interactions. To give a complete impression about the pyrimidine derivatives, compound 7 was subjected to 1,000 ps molecular dynamics (MD) simulations. The best structure based on our study was suggested for a future new drug with potential antimalarial compounds. © 2019 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim