Pharmacophore modeling of Tyrosine Kinase inhibitors: 4-anilinoquinazoline derivatives

A pharmacophore model for the inhibition of Tyrosine Kinase is established that could serve as a guide for the rational design of high potent and selective inhibitors. Recently, quantitative structure-activity relationships for 4-anilinoquinazoline class of inhibitors to inhibit EGFR autophosphorylation are in great demand. We have developed a quantitatively predictive chemical function-based pharmacophore model by using Discovery Studio 2.1 software. The optimal hypothesis consists of four features: three hydrophobic (HYD), and one hydrogen bond donor (HBD) functions. The input for HypoGen was a training set of 16 compounds exhibiting IC50 values ranging between 0.025 nM and 12000 nM, and having the output borne significant conventional coefficient of 0.97. To further validate our design rationale, protein- ligand docking software was used to elucidate the intra-molecular interactions. Therefore, the established pharmacophore model could help to a better understanding on how the substituents might influence the activity and afford important information for both ligand-based and structure-based drug designs.