Molecular docking and QSAR studies for modeling the antimalarial activity of hybrids 4-anilinoquinoline-triazines derivatives with the wild-type and mutant receptor pf-DHFR

Plasmodium falciparum dihydrofolate reductase (pf-DHFR) is one of the several targets in the treatment of malaria. Double and quadruple mutations at residues 51, 59, 108, and 164 of pf-DHFR have been linked to antifolate resistance. Several efforts are underway to overcome this drug resistance and to produce potential inhibitors. In this regard, the quantitative structure-activity relationship (QSAR) and docking studies were performed for previously reported 4-anilinoquinoline and 1,3,5-triazines based molecular hybrids. The generated model showed good correlation coefficients (R 2 = 0.70) and test set prediction coefficient (R 2 = 0.74). These outcomes showed the good predictive competence of the established QSAR model. Based on these results we docked into active site of pf-DHFR protein with the most active ( 4 ) and the less active ( 5 ) compounds. The docking results revealed that these molecules interact specifically with SER108 and ILE164 in the pf -DHFR binding pocket as that of best active compound but also showed additional interactions with LEU40 and GLY44.