Design of novel imidazo[1,2-a]pyrimidines as Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) inhibitors using fragment-based and other integrated in silico approaches.

Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) is a well-established target for developing novel antimalarial agents. Novel imidazo[1,2-a]pyrimidines were designed as PfDHODH inhibitors using a fragment-based drug design (FADD) approach. A library of active molecules targeting PfDHODH was analysed to generate fragments using the RDKit BRICS module. These fragments were screened by docking them into the active site of the PfDHODH enzyme. Among them, the lead fragment, fragment-11, demonstrated a significant binding affinity of -6.895 kcal/mol. This fragment was optimized using a fragment-growing approach via the FragGrow webserver. From the 471 generated molecules, two showed binding scores of -7.9 and -7.0 kcal/mol. These molecules were further optimized, resulting in a lead molecule with a binding score of -11.3 kcal/mol. Based on the results from the FragGrow webserver, 216 novel imidazo[1,2-a]pyrimidines were designed using the scaffold-hopping approach. The ADMET properties of these compounds revealing that all the designed compounds exhibited drug-like properties. Docking studies indicated that compounds 28d, 46d, and 49d had strong binding affinities, with 28d showing the highest score of -10.41 kcal/mol. Furthermore, molecular dynamics (MD) simulations of 28d demonstrated good stability in the enzyme-ligand complex. This comprehensive in silico study suggests that imidazo[1,2-a]pyrimidines can serve as potent PfDHODH inhibitors.