Identification of dual kinase inhibitors of CK2 and GSK3β: combined qualitative and quantitative pharmacophore modeling approach

Abstract

PTEN, a tumor suppressor protein, gets deactivated by casein kinase 2 (CK2) and glycogen synthase kinase 3β (GSK3β), which are the major causes of PI3K/AKT-driven tumors. To surmount this problem, the multi-target inhibitor strategy may be of great significance. The goal of this study was to design dual-target inhibitors of CK2 and GSK3β using a combination of pharmacophore modeling and molecular docking studies. The common feature-based (qualitative) and 3DQSAR-based (quantitative) pharmacophore models were generated and validated. The best pharmacophore models (Pharm18 and Hypo1) comprised two hydrogen-bond acceptors, one hydrophobic, and one ring aromatic features. The models were used to screen various chemical database and top mapped compounds from each database were selected. They were processed for Lipinski filter, Absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) analysis, and docking studies. We have obtained six hits with comparable dock score to the reported inhibitors. We have concluded Hit15 as a competent candidate based on its docking and Density Functional Theory (DFT) calculations. It showed 140.73 and 130.79 dock score in CK2 and GSK3β, respectively. The electronic property of Hit 15 showed the lowest energy gap (0.021) compared to other hits and active ligands which suggest its higher reactivity. In conclusion, this study may assist in the development of new potent dual kinase inhibitors of CK2 and GSK3β. Also, the overture effort of combined qualitative and quantitative modeling for the development of multi-target inhibitors may support the future endeavors.