Application of Machine Learning Algorithms to Metadynamics for the Elucidation of the Binding Modes and Free Energy Landscape of Drug/Target Interactions: a Case Study.

In the context of drug discovery, computational methods were able to accelerate the challenging process of designing and optimizing a new drug candidate. Amongst the possible atomistic simulation approaches, metadynamics (metaD) has proven very powerful. However, the choice of collective variables (CVs) is not trivial for complex systems. To automate the process of CVs identification, two different machine learning algorithms were applied in this study, namely DeepLDA and Autoencoder, to the metaD simulation of a well-researched drug/target complex, consisting in a pharmacologically relevant non-canonical DNA secondary structure (G-quadruplex) and a metallodrug acting as its stabilizer, as well as solvent molecules.