Virtual screening and docking of potential protein kinase B inhibitors

Abstract

This study aims to carry out a molecular docking process of novel ATP competitive inhibitors for protein kinase B-beta (PKBβ / AKT-2), activation of which has been observed in 30-40% of ovarian and pancreatic cancers. 3D pharmacophore filtering by Phase and multistep docking and scoring by Glide were applied to two different conformations of AKT-2 to take into account the conformational change upon binding of different inhibitors. The molecule library CoCoCo was screened to find hits. The procedure employed here combines the pharmacophore building and database screening methods, considers the protein conformation change upon binding by using two different protein conformations and also takes into account the solvation effect by including conserved water molecules in the active site. The top ranked molecules were further analyzed according to their interactions with AKT-2 and the final docking results from Glide were compared with previously identified inhibitors based on structure and chemistry. As a main contribution, ten putative inhibitors were proposed and analyzed for absorption, distribution, metabolism, and excretion (ADME) properties and selectivity for PKB-β.