Machine Learning Enabled Structure-Based Drug Repurposing Approach to Identify Potential CYP1B1 Inhibitors.

Drug-metabolizing enzyme (DME)-mediated pharmacokinetic resistance of some clinically approved anticancer agents is one of the main reasons for cancer treatment failure. In particular, some commonly used anticancer medicines, including docetaxel, tamoxifen, imatinib, cisplatin, and paclitaxel, are inactivated by CYP1B1. Currently, no approved drugs are available to treat this CYP1B1-mediated inactivation, making the pharmaceutical industries strive to discover new anticancer agents. Because of the extreme complexity and high risk in drug discovery and development, it is worthwhile to come up with a drug repurposing strategy that may solve the resistance problem of existing chemotherapeutics. Therefore, in the current study, a drug repurposing strategy was implemented to find the possible CYP1B1 inhibitors using machine learning (ML) and structure-based virtual screening (SB-VS) approaches. Initially, three different ML models were developed such as support vector machines (SVMs), random forest (RF), and artificial neural network (ANN); subsequently, the best-selected ML model was employed for virtual screening of the selleckchem database to identify potential CYP1B1 inhibitors. The inhibition potency of the obtained hits was judged by analyzing the crucial active site amino acid interactions against CYP1B1. After a thorough assessment of docking scores, binding affinities, as well as binding modes, four compounds were selected and further subjected to