Classification of substrates and inhibitors of P-glycoprotein using unsupervised machine learning approach

P-glycoprotein (P-gp), a drug efflux pump, affects the bioavailability of therapeutic drugs and plays a potentially important role in clinical drug-drug interactions. Classification of candidate drugs as substrates or inhibitors of the carrier protein is of crucial importance in drug development. Accurate classification is difficult to achieve due to two major factors: i. The extreme diversity of substrates and the presence of multiple binding sites complicate the understanding of the mechanisms behind and hinder the development of a true, conclusive quantitative structure-activity relationship (QSAR) for P-gp substrates. ii. Both inhibitors and substrates interact with the same binding site of P-gp, as a result, it is not surprising that both share many common structural features. In this work, an unsupervised machine learning approach based on the Kohonen self-organizing maps (SOM) was explored, which incorporated a predefined set of physicochemical descriptors encoding the key molecular properties capable of discerning a substrate from an inhibitor. The SOM model can discriminate between substrates and inhibitors with an average accuracy of 82.3%. The current results show that the SOM-based method provides a potential in silico model for virtual screening.