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ID: ALA5137020

Journal: J Med Chem

Title: Electrostatic Complementarity in Structure-Based Drug Design.

Authors: Cons BD, Twigg DG, Kumar R, Chessari G.

Abstract: Optimization of electrostatic complementarity is an important strategy in structure-based drug discovery for improving the affinity of molecules against a specific protein target. In this Miniperspective we identify examples where deliberate optimization of protein-ligand electrostatic complementarity or intramolecular electrostatic interactions gave improvements in target affinity (up to 250-fold), physicochemical properties, in vitro properties, and off-target selectivity. We also look retrospectively at a series of factor Xa inhibitors that show an almost 8000-fold range in potency that can be correlated with the calculated electrostatic potential (ESP) surfaces. Recent developments using a graph-convolutional deep neural network to rapidly generate high quality ESP surfaces have the potential to make this useful tool more accessible for a wider audience within the field of medicinal chemistry.

CiteXplore: 35512344

DOI: 10.1021/acs.jmedchem.2c00164