Integrated computational investigation to develop molecular design of quinazoline scaffold as promising inhibitors of plasmodium lactate dehydrogenase

Abstract

An integrated computational approach has been applied to a series of quinazoline derivatives to identify a potentially efficacious agent for malarial therapy. The best QSAR model has a good predictive correlation coefficient (r2) of 0.7908 and a significant Leave-one-out cross-validated correlation coefficient (q2) of 0.7232. Pharmacophore mapping results highlighted that 2-4- di substituted quinazoline derivative is an essential feature for the antimalarial activity. New molecules were designed based on above results and finally screened through docking tool and binding affinities of designed molecules were studied on the plasmodium lactate dehydrogenase enzyme. Docking studies revealed that carbonyl group act as a hydrogen acceptor region and 4-amino group of designed molecules act as a hydrogen donor region which facilitates hydrogen bonding with ASP-53, TYR-85 and GLU-122. Further, three complexes, i.e. chloroquine and best two docked complexes M9 and M14 were selected for molecular dynamics simulation studies. RMSD and RMSF analysis revealed that all complexes were quite stable throughout 20ns time period below 2 Å. Additionally, MM-GBSA analysis computes binding free energy suggested that ligand M14 has the highest binding energy (ΔGtotal = −34.34 kcal/mol) towards plasmodium lactate dehydrogenase as compared to a reference chloroquine molecule (ΔGtotal = −29.29 kcal/mol). In silico ADME studies revealed that the designed molecules were potential orally bioavailable drug like molecules. Thus, these studies suggest that established models have good predictive ability and designed molecules may elicit potent antimalarial activity.