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Analysis of electrostatic interactions

Quantify electrostatically driven SAR and predict electrostatic target selectivity
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Cresset has combined the analysis of ligand electrostatics with that of protein electrostatics to generate a visual and numerical assessment of the Electrostatic Complementarity™ (EC) of ligand protein complexes. The Cresset EC method is computationally inexpensive and can be applied to large data sets. We have analysed both the visual and numerical components by applying the method to a range of literature sets, showing that it correlates with and can predict reported bioactivity differences – see our paper in J. Med Chem. EC analysis has also been applied to kinase selectivity prediction, streptavidin mutant analysis and selection of ligand protonation states in protein context. The results of this work have shown that assessing EC can be a powerful tool for analysis and optimization of electrostatic protein-ligand interactions, making it possible to quantify electrostatically driven SAR and predict electrostatic target selectivity. The Cresset protein-ligand EC is calculated from comparison of protein and ligand electrostatic potential (ESP) values at all vertices of a generated ligand or protein solvent accessible surface (SAS) [1,2]. Perfect electrostatic complementarity would mean that at each vertex the ligand ESP value would be paired with a protein ESP value of the same magnitude with reverse sign. Below is a visualization of both ESP and EC of the biotin-streptavidin complex on both ligand and protein SAS, showing how a close matching of positive and negative electrostatic potential areas of protein and ligand leads to a good EC.

Below, we calculate an EC score that provides an approximate correction for some desolvation effects and allows local visualization of EC on a protein or ligand solvent-accessible surface where the integral is over the ligand SAS, ESPL and ESPP, the ligand and protein ESP values, and MAX(ESPL,ESPP,k) the protein or ligand ESP value with the larger deviation from zero, or a constant k if that is larger. Ligand and protein ESP values are capped to the maximum ESP values observed for water molecules to approximately correct for desolvation. EC scores range from 1 to -1, corresponding to a perfect EC or complete electrostatic clash, respectively. As solvent-exposed portions of the ligand contribute less information about the electrostatic complementarity of protein-ligand complexes, regions of the ligand SAS that are more than 3 Å away from any protein atom are scaled down by a distance-dependent factor.

The Cresset EC method has been applied to a reported XIAP-BIR3 data set, demonstrating that this method can detect and quantify electrostatic differences in XIAP ligands that cause changes in bioactivity.

References

  1. Xu, D.; Li, H.; Zhang, Y. Protein Depth Calculation and the Use for Improving Accuracy of Protein Fold Recognition. J Comput Biol 2013, 20 (10), 805–816. https://doi.org/10.1089/cmb.2013.0071.
  2. Xu, D.; Zhang, Y. Generating Triangulated Macromolecular Surfaces by Euclidean Distance Transform. PLoS ONE 2009, 4 (12), e8140. https://doi.org/10.1371/journal.pone.0008140.

What our customers say

“As a global computational chemistry team within a contract research organisation (CRO), we aimed to improve the consistency, scalability, and scientific rigor of our molecular modelling workflows across a wide range of client projects. Cresset supported a smooth transition from a previously used commercial tool and helped address key limitations around accessibility and deployment at scale. A differentiated licensing model has enabled broad access across chemistry and biology teams while reserving advanced capabilities for computational chemistry specialists. This approach has helped balance accessibility, scientific depth, and efficient use of resources, enabling wider engagement without compromising rigor. The Cresset team have been highly responsive and knowledgeable, working closely with us to support adoption across a global user base. Training was organised according to user needs, with regular office hours providing an open forum for questions and ongoing support.

Overall, Cresset has become a valuable part of our computational chemistry toolkit, strengthening consistency, productivity, and confidence in decision-making across our organisation.”

Nicola Porta, Senior Scientist, Evotec

We are pleased to be working with Cresset’s software. This provides us with intuitive molecule design, a powerful ability to understand SAR and design plus a fresh way for generating novel and diverse structures for our projects.

Dr Kristian Birchall, Medical Research Council Technology, UK

We really like the powerful combination of excellent software tools and molecular design expertise which we get from working with Cresset.

Dr Graham Sibley, Head of Chemistry, F2G, UK

We wanted to use computational methods to suggest alternative substructures which could replace part of one of our key leads. We’d looked at other tools previously, without success, then turned to the Spark™ field-based approach. We looked at the top 50 hits from Spark and selected a subset to synthesise. Whilst the synthesised compounds exhibited a broad range of activities, we were delighted to observe that a number turned out to be nanomolar hits – with several even more potent than the original lead. One of these compounds is now our key lead against this target and further analogue synthesis is underway. Spark has certainly helped direct us towards some novel and very useful SAR on this occasion.

Laurent Rigoreau, Group Leader Medicinal Chemistry, Cancer Research Technology Discovery Laboratories

Cresset Discovery’s computational experience and high standard of scientific support is ideally suited to help drive the next stage of this project.

Dr Richard Boyce, Senior Director of Research, PhoreMost

The protein interaction potential capability [in Flare] highlighted common features across the family of targets of interest that we had not been able to visualize before. We used this information to drive ligand design into a direction we have not explored before.

Dr Martin Quibell, MAQU Chemistry Consulting, UK

We sought the scientific expertise within the Cresset Discovery team to utilize their novel field and shape-based virtual screening methods in Blaze™, and their proprietary Electrostatic Complementarity™ technique to help identify a backup series for our target effectively and efficiently. Ultimately we identified 9 novel chemotypes that were clearly distinct to those arising from docking and pharmacophore virtual screening approaches, which was an exciting outcome for us.

Dr Zara Sands, Head of CADD and Informatics, Confo Therapeutics, Belgium

Working closely with the Cresset Discovery team we aimed to identify a putative binding pose for a lead series in published PDB coordinates that was not only consistent with the kinetically deduced MOA but explained the established SAR as well. The furnished results were able to satisfy these goals and then be applied prophetically for ligand design purposes.

Twentyeight-Seven Therapeutics, USA

Medicinal chemists in my team find the covalent docking feature in Flare™ very intuitive to use.

Matthias Bauer, AstraZeneca, UK