Issue 3, 2022

Application of site-identification by ligand competitive saturation in computer-aided drug design

Abstract

Site Identification by Ligand Competitive Saturation (SILCS) is a molecular simulation approach that uses diverse small solutes in aqueous solution to obtain functional group affinity patterns of a protein or other macromolecule. This involves employing a combined Grand Canonical Monte Carlo (GCMC)-molecular dynamics (MD) method to sample the full 3D space of the protein, including deep binding pockets and interior cavities from which functional group free energy maps (FragMaps) are obtained. The information content in the maps, which include contributions from protein flexibility and both protein and functional group desolvation contributions, can be used in many aspects of the drug discovery process. These include identification of novel ligand binding pockets, including allosteric sites, pharmacophore modeling, prediction of relative protein–ligand binding affinities for database screening and lead optimization efforts, evaluation of protein–protein interactions and formulation of biologics-based drugs including monoclonal antibodies. The present article summarizes the various tools developed in the context of the SILCS methodology and their utility in computer-aided drug design (CADD) applications, showing how the SILCS toolset can improve the drug-development process on a number of fronts with respect to both accuracy and throughput representing a new avenue of CADD applications.

Graphical abstract: Application of site-identification by ligand competitive saturation in computer-aided drug design

Article information

Article type
Perspective
Submitted
23 aug 2021
Accepted
19 nov 2021
First published
29 nov 2021

New J. Chem., 2022,46, 919-932

Application of site-identification by ligand competitive saturation in computer-aided drug design

H. Goel, A. Hazel, W. Yu, S. Jo and A. D. MacKerell, New J. Chem., 2022, 46, 919 DOI: 10.1039/D1NJ04028F

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements