Electrostatic Similarities between Protein and Small Molecule Ligands Facilitate the Design of Protein-Protein Interaction Inhibitors

Arnout Voet,Kam Y. J. Zhang,Francois Berenger,Andreas Hofmann

doi:10.1371/journal.pone.0075762

Arnout Voet, Kam Y. J. Zhang + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0075762

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Journal: PloS one	Publication Date: Oct 10, 2013
Citations: 22	License type: CC BY 4.0

Affiliation: RIKEN

Abstract

One of the underlying principles in drug discovery is that a biologically active compound is complimentary in shape and molecular recognition features to its receptor. This principle infers that molecules binding to the same receptor may share some common features. Here, we have investigated whether the electrostatic similarity can be used for the discovery of small molecule protein-protein interaction inhibitors (SMPPIIs). We have developed a method that can be used to evaluate the similarity of electrostatic potentials between small molecules and known protein ligands. This method was implemented in a software called EleKit. Analyses of all available (at the time of research) SMPPII structures indicate that SMPPIIs bear some similarities of electrostatic potential with the ligand proteins of the same receptor. This is especially true for the more polar SMPPIIs. Retrospective analysis of several successful SMPPIIs has shown the applicability of EleKit in the design of new SMPPIIs.

Highlights

With the advent of the ‘omics’ era, it has become clear that most proteins do not act in solitude but depend on Protein-Protein Interactions (PPIs) to exert their biological function
A recent example of the usefulness of taking electrostatic potential similarity into account while designing an small molecule PPI inhibitors (SMPPIIs) can be found in the work of Cavalluzo et al [31], where an SMPPII was designed de novo by including electrostatic similarity. This success has motivated our effort to systematically investigate the complementarity in electrostatic potential between small molecules and protein ligands binding to the same protein receptor, and its potential use to assist in the rational design of SMPPIIs
The EleKit method was applied to analyze previously reported cases of SMPPIIs, for which accurate structures of the PPI as well as the SMPPII receptor complex are available in the PDB

Summary

Introduction

With the advent of the ‘omics’ era, it has become clear that most proteins do not act in solitude but depend on Protein-Protein Interactions (PPIs) to exert their biological function. It can still be assumed that there is some local electrostatic potential similarity between an SMPPII and a ligand protein, since they recognize the same binding site on the receptor. This success has motivated our effort to systematically investigate the complementarity in electrostatic potential between small molecules and protein ligands binding to the same protein receptor, and its potential use to assist in the rational design of SMPPIIs. For this purpose, a tool named EleKit was developed.

Results

Conclusion