Topomer-CoMFA study of tricyclic azepine derivatives-EGFR inhibitors

Abstract

EGFR has been intensively investigated as a target to block the signal transduction pathway which stimulates cancer growth and metastasis. Studies about structure-activity relationship for tricyclic azepine derivatives were performed with topomer-CoMFA. The derived topomer-CoMFA model with steric and electrostatic field parameters based on fragment units gave reasonable statistics (q(2)=0.561, r(2)=0.679). The model explains why a halogen atom at the meta position of aniline is important to increases inhibitory activity. This comes from an electrostatically negative groups are favored near this region. The model also shows that there are sterically favored regions around methoxy group extended from oxazepine derivatives. The findings about steric and electrostatic effects can be utilized for designing new inhibitors.