Rational design of novel 2-aminopyrido[3,4-d]pyrimidin-4-one derivatives as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors using 3D QSAR, docking, molecular dynamics simulation approaches

Plasmodium falciparum dihydroorotate dehydrogenase ( Pf DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway and a validated antimalarial drug target. Inhibition of Pf DHODH enzyme disrupts nucleotide synthesis, which leads to parasite death. Field-based 3D QSAR models were developed using a dataset of 75 Pf DHODH inhibitors to identify key features interacting with the active site of the enzyme. Partial least squares (PLS) analysis was performed, and contour-map interpretation guided the design of new 2-aminopyrido[3,4- d ]pyrimidin-4-one derivatives. The activity (pIC 50 ) values of designed compounds were predicted using the PLS model-5. Drug-likeness and pharmacokinetic profiles of the designed compounds were evaluated through in silico ADMET prediction study. Molecular docking studies were performed for the designed compounds using AutoDock Vina 1.2.7 with the Pf DHODH crystal structure. Further, the compound with the best docking score was evaluated for stability using 200 ns molecular dynamics simulations and MM/GBSA calculations with gmx_MMPBSA tools. The 3D QSAR model exhibited good statistical reliability with R 2 of 0.9 and Q 2 of 0.805. The generated contour maps were used for the design of new 2-aminopyrido[3,4- d ]pyrimidin-4-one derivatives. These analogues showed moderate predictive activity (pIC 50 ) in the range of 7.3–7.741. In silico ADMET evaluation showed that the designed molecule has acceptable drug-likeness and pharmacokinetic profiles. Docking studies revealed that compound 2d showed the highest docking score (-9.541 kcal/mol) and formed key interactions similar to those observed in the reference inhibitor DSM265 (-9.326 kcal/mol). MD simulation studies confirmed that compound 2d showed good stability of the complex with Pf DHODH over the 200 ns trajectory and with MM/GBSA calculations. These results suggest that the designed compounds have the potential to act as Pf DHODH inhibitors and antimalarial agents. A novel series of 2-aminopyrido[3,4- d ]pyrimidin-4-one will be synthesized and further evaluated experimentally for Pf DHODH inhibition and antimalarial activity.