3D-QSAR Studies on a Series of 2,4-Thiazolidinedione Derivatives: A Self- Organizing Molecular Field Analysis Approach to Design Novel PTP 1B Inhibitors

Diabetes mellitus is a group of metabolic disorders characterised by chronic hyperglycemia resulting either from a deficiency of insulin, or decreased ability to transduce the insulin signal, or both. Insulin resistance and β-cell dysfunction are two fundamental defects known to precede the onset of type 2 diabetes. PTP 1B is considered to function as a negative regulator of insulin signal transduction by dephosphorylating phosphotyrosine residues. 2,4-Thiazolidinediones (TZDs) have long been considered as antihyperglycemic agents which act by ameliorating insulin resistance and thereby normalizing elevated blood glucose level. A three dimensional quantitative structure-activity relationship (3D-QSAR) study was performed on a novel class of thiazolidinedione derivatives using self-organizing molecular field analysis (SOMFA) to correlate their molecular architecture with observed PTP 1B inhibitory activities. The master grid maps derived from the best model were used to display the contribution of both electrostatic and shape potential that can be mapped back onto structural features relating to the trends in inhibitory activities. The present SOMFA study indicated the indispensable molecular features which can be further explored for structural modifications of these lead molecules in order to optimize PTP 1B inhibitory activity.