Combining machine learning, molecular dynamics, and free energy analysis for (5HT)-2A receptor modulator classification

The 5-Hydroxytryptamine (5HT)-2A receptor, a key target in psychoactive drug development, presents significant challenges in the design of selective compounds. Here, we describe the construction, evaluation and validation of two machine learning (ML) models for the classification of bioactivity mechanisms against the (5HT)-2A receptor. Employing neural networks and XGBoost models, we achieved an overall accuracy of around 87 %, which was further enhanced through molecular modelling (MM) (e.g. molecular dynamics simulations) and binding free energy analysis. This ML-MM integration provided insights into the mechanisms of direct modulators and prodrugs. A significant outcome of the current study is the development of a ‘binding free energy fingerprint’ specific to (5HT)-2A modulators, offering a novel metric for evaluating drug efficacy against this target. Our study demonstrates the prospective of employing a successful workflow combining AI with structural biology, offering a powerful tool for advancing psychoactive drug discovery.