Induced fit docking, pharmacophore modeling, and molecular dynamic simulations on thiazolidinedione derivatives to explore key interactions with Tyr48 in polyol pathway.

To obtain a scientific thought and expedition to explore key interactions with Tyr48 in aldose reductase (ALR), combined study of pharmacophore modeling, induced fit docking, and dynamics studies were performed on ALR. A stereo chemically and energetically valid model of ALR-NADP+ complex was developed using homology modeling technique. Statistically a significant five point pharmacophore model was designed on a set of 54 thiazolidinedione derivatives with good external and internal predictive ability. Rigid and induced fit docking protocols were applied on ALR protein for both with and without NADP+ cofactor to identify a suitable binding mode that facilitates the key hydrogen bond interactions with Tyr48. Docking of thiazolidinedione derivatives into ALR-NADP+ complex gave more promising results by reducing false positive binding of inhibitors into the co-factor binding site. Structural changes within Try48 and Asp43 during the binding process in enzyme inhibitor complex were analyzed using molecular dynamics (MD) simulations. The results obtained from dynamic simulations emphasized the role of Tyr48 in maintaining inter or intra molecular hydrogen bond interaction with the protein or inhibitor respectively. New molecules were designed and checked for their binding interactions and showed improved results compared to existing thiazolidinediones derivatives. Hence, these combined protocols will be helpful and cooperative to design and optimize molecules with better inhibitory activity against the biologically active target.