Structure-based CoMFA and CoMSIA study of indolinone inhibitors of PDK1

Abstract

Phosphoinositide-dependent protein kinase-1 (PDK1) is a Ser/Thr kinase which phosphorylates and activates members of the AGC kinase group known to control processes such as tumor cell growth, protection from apoptosis, and tumor angiogenesis. In this paper, CoMFA and CoMSIA studies were carried out on a training set of 56 conformationally rigid indolinone inhibitors of PDK1. Predictive 3D QSAR models, established using atom fit alignment rule based on crystallographic-bound conformation, had cross-validated (r ²_cv ) values of 0.738 and 0.816 and non-cross-validated (r ²_ncv ) values of 0.912 and 0.949 for CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 14 compounds, which gave predictive correlation coefficients (r ²_pred ) of 0.865 and 0.837, respectively. Structure-based interpretation of the CoMFA and CoMSIA field properties provided further insights for the rational design of new PDK1 inhibitors.