Development of pharmacophore model for a series of indenoindoles as protein kinase CK2 inhibitors.

Haidar S, Le Borgne M, Jose J

Abstract

CK2 Casein kinase 2 is a ubiquitously expressed kinase protein emerging as a target for the treatment of cancer. Several active CK2 inhibitors have been developed in the last few years; most of them have ATP-competitive type of inhibition. Most of the CK2 consist of small and planar heterocyclic scaffolds with different substituent mimicking the adenine or the purin of the ATP. Those compounds are expected to fit into the nucleotide-binding pocket of CK2. Indenoindoles present a class of natural and synthetic compounds; many of them have different bioactivity. Here we report on the development of a ligand-based pharmacophore on the basis of different active indenoindoles (training set), the pharmacophore model was challenged against small library of indenoindoles (test set), the study was performed using MOE software. Our model demonstrates a good performance in the test set, 80% of the medium or high inhibitory activity compounds were identified, while only 16% of the low or no inhibitory activity compounds were misclassified. The results proved that our pharmacophore model is a filter of good sensitivity and specificity. Several structures were suggested as possible active CK2 inhibitors by using this model as a base for search in the ZINC database.