Hybrid consensus and k-nearest neighbours (kNN) strategies to classify dual BRD4/PLK1 inhibitors.

A novel decision-making procedure is proposed here for the first time to identify active/inactive and selective/non-selective dual inhibitors using consensus approaches and pools of k-nearest neighbours (kNN) classifications instead of individual models. Dual BRD4/PLK1 inhibition with adequate selectivity is a potential therapeutic strategy for targeting tumour cells in high-risk patients. We report the unique way to identify both active and selective dual BRD4/PLK1 inhibitors using consensus and kNN strategies together with two sources of receptor-based and ligand-based information which are the ranked binding energies of residues and important molecular features, respectively. The results of consensus approaches were compared with the results of individual kNN models. The chemical space similarity was measured using three different distance functions to increase the reliability. All activity and selectivity classification models were validated using cross-validation and y-randomization tests. The outcomes show that consensus approaches can increase the reliability and accuracy of active/inactive or selective/non-selective detections up to 90%. Consensus approaches also reached more balanced values of sensitivity and specificity compared to the individual kNN models because of the compensation in the integration of diverse sources of information.