De novo design of PLK1 inhibitors based on 2-amino aromatic heterocyclic scaffold: 3D-QSAR and molecular fragment replacement

Abstract

Polo-like kinase 1 (PLK1) has emerged as an important drug target for developing novel anticancer drugs. To design compounds with enhanced inhibitory potency against PLK1, pharmacophore modelling, three-dimensional quantitative structure–activity relationship and molecular fragment replacement were performed on three classes of PLK1 inhibitors (pyrazolopyridines, isoxazolopyridines and imidazotriazines) that have analogous scaffolds. The comparative molecular field analysis (CoMFA) models were developed using the ligand-based and receptor-based pharmacophore alignments, respectively. Taking advantage of the insights gained from CoMFA study, two important points of the scaffolds were replaced with diverse molecular fragments to design new compounds. After filtered with the pharmacophore derived from BI-2536 and predicted by the CoMFA model, 11 promising compounds with high-estimated bioactivities were finally obtained. These results will not only provide meaningful insight into the relationship between PLK1 and inhibitors, but also promote the de novo design of new compounds against PLK1.