Can Quantum Chemistry Improve the understanding of Protein-Ligand Interactions? Implications for Structure Based Drug Discovery

Abstract

We introduce an Energy Decomposition Analysis suitable for understanding the nature of non-covalent binding in large chemical systems, like those of drug-protein complexes. The method is atom specific, thus allowing rationalization of the role that each atom or functional group plays for the interaction. Visual representations are constructed in the form of interaction maps, depicting the different contributions for electrostatics, polarization, dispersion (lipophilicity), etc. This marks the departure from atomistic models towards electronic interaction ones, that better correlate with experimental data. The maps provide a quick access to the driving forces behind the formation of intermolecular complexes, and the key contributors for each interaction. This allows constructing quantum mechanical models of binding. The presented method is validated against experimental binding data for the difficult to target protein-protein interface for PEX14-PEX5 and its inhibitors.