Molecular docking assisted 3D-QSAR study of benzylidene-2,4-thiazolidinedione derivatives as PTP-1B inhibitors for the management of Type-2 diabetes mellitus

Insulin resistance is the pathophysiological factor behind the etiology and progression of Type 2 diabetes mellitus (T2DM), a metabolic syndrome that is continuously increasing in prevalence worldwide, associated with the overexpression of protein tyrosine phosphatase (PTP-1B). PTP-1B acting as a negative regulator of insulin as well as leptin signaling pathways, contributing to insulin and leptin resistance, which are both responsible for 'diabesity', i.e. diabetes with obesity. The marketed antihyperglycemic drug pioglitazone is a benzyl-2,4-thiazolidinedione derivative with substitution on the phenyl ring. The literature also shows that benzylidene-2,4-thiazolidinedione derivatives exhibit selective and potent PTP-1B inhibitory activity. Therefore, there is an urge to investigate the pharmacophoric features of the widely explored scaffold benzylidene-2,4-thiazolidinedione against PTP-1B for its selectivity and potency using computer aided drug design tools. In the present study, a molecular docking assisted three dimensional quantitative structure activity relationship (3D-QSAR) study was performed on a diverse series of benzylidene-2,4-thiazolidinedione derivatives with wide range of PTP-1B inhibitory activity. Molecular docking explores the binding interactions between the lowest energy conformations of the molecules and the key amino acid residues present in the binding site of PTP-1B. The present study generates spatial fingerprints, which will be useful for future pharmacophoric amendments of benzylidene-2,4-thiazolidinedione derivatives towards the development of novel PTP-1B inhibitors.