Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition and are also key contributors to the binding free energy ΔG. Assessing the electrostatic match of protein-ligand complexes therefore provides important insights into why ligands bind and what can be changed to improve binding. Ideally, corresponding ligand and protein electrostatic potentials at the protein-ligand interaction interface should be complementary while minimizing desolvation penalties. In this work, we present a fast and efficient tool to visualize and calculate the electrostatic complementarity (EC) of protein-ligand complexes. The electrostatic calculations use the polarizable Extended Electron Distribution (XED) force field, which can describe atomic charge anisotropy, and employ a distance dependent dielectric to avoid overemphasis of formal charges. Using several benchmark sets compiled from mainly electrostatically driven SAR, including data of the PPI target XIAP and the GPCR mGLU5, we demonstrate that our EC method can visualize, rationalize, and predict electrostatically driven ligand affinity changes, aid selection of ligand protonation states, and help to predict compound selectivity. The methodology presented here for analysis of electrostatic complementarity is a powerful and versatile tool for drug design.

Electrostatic complementarity as a fast and effective tool to optimize binding and selectivity of protein-ligand complexes

2019 Spring National Meeting

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