Discovery of some potent PDHK inhibitors using pharmacophore modeling, virtual screening and molecular docking studies

Abstract

A pharmacophore model has been generated and 3D-QSAR studies performed on a set of fifty fluorinated compounds having known activities for PDHK inhibition (IC­­₅₀ values ranging from 0.1 µmol L^-1 to 100.0 µmol L^-1). Common pharmacophore hypotheses have been developed and a predictive atom based 3D-QSAR model is further generated for all the surviving hypotheses. All the statistical parameters calculated for the obtained model (AHH.2) have been found to be satisfactory. The model obtained suggests that the presence of hydrophobic groups and ability to form hydrogen bonds are the two vital features which play significant roles in the activity of the selected ligands. The binding site of the protein is hydrophobic in nature and hence the presence of –F in the binding compounds enhances their inhibiting property. An excellent correlation between the calculated and experimental IC­₅₀ values of the compounds has been obtained. Virtual screening of a database comprising 2924 commercially available drug molecules has been performed to ensure the validity of the model developed. A total of 1263 compounds, which show good fit to the model, have been docked to the PDHK protein for further study of their binding affinities and interaction with the protein. A few of these are short-listed for further evaluation.