Theoretical studies of Thiazolyl-Pyrazoline derivatives as promising drugs against malaria by QSAR modelling combined with molecular docking and molecular dynamics simulation

Abstract

ABSTRACT We investigate thiazolyl-pyrazoline derivatives as promising drugs for the anti-malarial. Protein kinase G is a primary target for treating malaria due to its essential role in Plasmodium falciparum life cycle. In this present study, several computational approaches such as QSAR modelling, molecular docking, and all-atom MD simulation are performed to screen 36 drug candidates against malaria. From QSAR analysis, three potent drugs are selected based on the strong correlation between the inhibitory action, i.e. pEC50 and various descriptors. Further, those selected drugs are used as ligand molecules for molecular docking. We predict three complexes of models 1, 2, and 3 bind to the catalytic site of protein kinase G, suggesting those ligands may become potent inhibitors for Plasmodium falciparum. To validate the structural stability of those complexes, the parameters of RMSD, RMSF, and Rg are calculated from MD simulation. All models are stable along simulation since no significant fluctuations are observed in those validity parameters. Moreover, the binding energy is estimated at each model using MM-GBSA method and model 2 becomes the most stable structure. Finally, three ligands are assumed to have potential as inhibitors and the ligand of model 2 may become the most promising drug against malaria.