Prediction of activity and selectivity profiles of human Carbonic Anhydrase inhibitors using machine learning classification models

The development of selective inhibitors of the clinically relevant human Carbonic Anhydrase (hCA) isoforms IX and XII has become a major topic in drug research, due to their deregulation in several types of cancer. Indeed, the selective inhibition of these two isoforms, especially with respect to the homeostatic isoform II, holds great promise to develop anticancer drugs with limited side effects. Therefore, the development of in silico models able to predict the activity and selectivity against the desired isoform(s) is of central interest. In this work, we have developed a series of machine learning classification models, trained on high confidence data extracted from ChEMBL, able to predict the activity and selectivity profiles of ligands for human Carbonic Anhydrase isoforms II, IX and XII. The training datasets were built with a procedure that made use of flexible bioactivity thresholds to obtain well-balanced active and inactive classes. We used multiple algorithms and sampling sizes to finally select activity models able to classify active or inactive molecules with excellent performances. Remarkably, the results herein reported turned out to be better than those obtained by models built with the classic approach of selecting an a priori activity threshold. The sequential application of such validated models enables virtual screening to be performed in a fast and more reliable way to predict the activity and selectivity profiles against the investigated isoforms. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13321-021-00499-y.