Key interactions of pyrimethamine derivatives specific to wild-type and mutant dihydrofolate reductase based on 3D-QSAR, MD simulations and quantum chemical calculations.

dihydrofolate reductase-thymidylate synthase (DHFR-TS) is an important target enzyme in malarial chemotherapy. An understanding of how novel inhibitors interact with wild-type (wtDHFR), quadruple-mutant (qmDHFR), and human (DHFR) enzymes is required for the development of these compounds as antimalarials. This study is focused on a series of -Cl and -Cl phenyl analogs of pyrimethamine with various flexible 6-substituents.