Electrostatic Complementarity as a Fast and Effective Tool to Optimize Binding and Selectivity of Protein-Ligand Complexes

Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition and are also key contributors to the binding free energy. Assessing the electrostatic match of protein-ligand complexes therefore provides important insights into why ligands bin...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 62; no. 6; p. 3036
Main Authors: Bauer, Matthias R, Mackey, Mark D
Format: Journal Article
Language:English
Published: United States 28.03.2019
Subjects:
Drug Design
Ligands
Protein Binding
Proteins - chemistry
Static Electricity
Structure-Activity Relationship
ISSN:1520-4804, 1520-4804
Online Access:Get more information
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Summary:Electrostatic interactions between small molecules and their respective receptors are essential for molecular recognition and are also key contributors to the binding free energy. 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, the ligand and protein electrostatic potentials at the protein-ligand interaction interface should maximize their complementarity while minimizing desolvation penalties. In this work, we present a fast and efficient tool to calculate and visualize the electrostatic complementarity (EC) of protein-ligand complexes. We compiled benchmark sets demonstrating electrostatically driven structure-activity relationships (SAR) from literature data, including kinase, protein-protein interaction, and GPCR targets, and used these to demonstrate that the EC method can visualize, rationalize, and predict electrostatically driven ligand affinity changes and help to predict compound selectivity. The methodology presented here for the analysis of EC is a powerful and versatile tool for drug design.
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ISSN:1520-4804
1520-4804
DOI:10.1021/acs.jmedchem.8b01925