Estimating protein-ligand interactions with geometric deep learning and mixture density models

Understanding the interactions between a ligand and its molecular target is crucial in guiding the optimization of molecules for any in silico drug design workflow. Multiple experimental and computational methods have been developed to better understand these intermolecular interactions. With the availability of a large number of structural datasets, there is a need for developing statistical frameworks that improve upon existing physicsbased solutions. Here, we report a method based on geometric deep learning that is capable of predicting the binding conformations of ligands to protein targets. A technique to generate graphical representations of proteins was developed to exploit the topological and electrostatic properties of the binding region. The developed framework, based on graph neural networks, learns a statistical potential based on the distance likelihood, which is tailor-made for each ligand-target pair. This potential can be coupled with global optimization algorithms such as differential evolution to reproduce the experimental binding conformations of ligands. We show that the potential based on distance likelihood, described here, performs similarly or better than well-established scoring functions for docking and screening tasks. Overall, this method represents an example of how artificial intelligence can be used to improve structure-based drug design.