Strategies to select the best pharmacophore model: a case study in pyrazoloquinazoline class of PLK-1 inhibitors

Polo like kinase-1 (PLK-1) is essential during mitosis and in the maintenance of genomic stability. Thus, PLK-1 can be a preferential target for inhibition of mitotic processing and hence can be chosen as a drug target for the treatment of cancer. The aim of the study was to develop and validate a pharmacophore model for PLK-1 inhibitors, which is able to reproduce the receptor bound conformation of the ligand as closely as possible. Out of 14 models which could reproduce the receptor-bound conformation of the ligand, two models performed well in the decoy set statistics. Final selection of the pharmacophore model was based upon the ability of the validated model to identify actives belonging to diverse chemical classes. The selected five-point pharmacophore model for a pyrazoloquinazoline class of PLK-1 inhibitors includes one hydrogen-bond donor (D), two hydrophobic features (H), one positively-charged feature (P), and one aromatic ring feature (R).