Studies on Substituted Thienopyridine Carbonitriles as Src Inhibitors Using a Comprehensive In Silico Method

Abstract

To explore the structural requirements and inhibitory mechanism of Src inhibitors, the comparative molecular field analysis, comparative molecular similarity indices analysis and three-dimensional quantitative structure-activity relationship and molecular docking of 45 substituted thienopyridine carbonitriles as tyrosine kinase pp60src inhibitors was conducted. Three three-dimensional quantitative structure-activity relationship models showed high predictabilities with cross-validated correlation coefficient and predictive correlation coefficient values of 0.793 and 0.887 for comparative molecular field analysis and 0.624 and 0.793 for comparative molecular similarity indices analysis, respectively. Docking results indicated that 4 compounds with high inhibitory activity penetrated into the active pocket of tyrosine kinase pp60src and formed stable hydrogen bonds with the binding pocket of tyrosine kinase pp60src. Leu273, Lys295, Thr338, Asp348, and Ser345 of tyrosine kinase pp60src are important residues. The results could be of great value in designing novel substituted thienopyridine carbonitriles with more potent Src kinase inhibitory activity.