Three-dimensional quantitative structure–activity relationship of 4,5,6,7-tetrahydrothienopyridines analogues as glucose-6-phosphatase inhibitors

A Three-Dimensional Quantitative Structure–activity Relationship (3D-QSAR) model that correlates the biological activities with the chemical structures of a series of Glucose-6-phosphatase inhibitors, exemplified by the 4,5,6,7-tetrahydrothienopyridines derivatives, was established by means of comparative molecular field analysis (CoMFA). The resulting leave-one-out cross-validated value (q2=0.600) and non-cross-validated value (r2=0.956) indicate that the obtained pharmacophore model indeed mimics the steric and electrostatic environment, where inhibitors bind to the enzyme. Furthermore, the developed model also possesses promising predictive ability as discerned by the testing on the external test set. The analysis of the CoMFA contour map, which reveal how steric and electrostatic interactions contribute to inhibitors' bioactivities, provide us with the important information to understand the molecular nature of inhibitor–enzyme interactions and to aid in the design of more potent Glucose-6-phosphatase inhibitors.