Fragment Hotspot Mapping to Identify Selectivity-Determining Regions between Related Proteins.
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Authors
Curran, Peter R
Radoux, Chris J
von Delft, Frank
Bradley, Anthony R
Publication Date
2022-01-24Journal Title
J Chem Inf Model
ISSN
1549-9596
Publisher
American Chemical Society (ACS)
Volume
62
Issue
2
Pages
284-294
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Smilova, M. D., Curran, P. R., Radoux, C. J., von Delft, F., Cole, J. C., Bradley, A. R., & Marsden, B. D. (2022). Fragment Hotspot Mapping to Identify Selectivity-Determining Regions between Related Proteins.. J Chem Inf Model, 62 (2), 284-294. https://doi.org/10.1021/acs.jcim.1c00823
Description
Funder: Exscientia
Funder: Diamond Light Source
Funder: Kungliga Tekniska Hoegskolan
Funder: Chinese Center for Disease Control and Prevention
Funder: European Federation of Pharmaceutical Industries and Associations
Funder: European Commission
Funder: Kennedy Trust for Rheumatology Research
Funder: Ontario Institute for Cancer Research
Funder: Royal Institution for the Advancement of Learning McGill University
Funder: UCB
Abstract
Selectivity is a crucial property in small molecule development. Binding site comparisons within a protein family are a key piece of information when aiming to modulate the selectivity profile of a compound. Binding site differences can be exploited to confer selectivity for a specific target, while shared areas can provide insights into polypharmacology. As the quantity of structural data grows, automated methods are needed to process, summarize, and present these data to users. We present a computational method that provides quantitative and data-driven summaries of the available binding site information from an ensemble of structures of the same protein. The resulting ensemble maps identify the key interactions important for ligand binding in the ensemble. The comparison of ensemble maps of related proteins enables the identification of selectivity-determining regions within a protein family. We applied the method to three examples from the well-researched human bromodomain and kinase families, demonstrating that the method is able to identify selectivity-determining regions that have been used to introduce selectivity in past drug discovery campaigns. We then illustrate how the resulting maps can be used to automate comparisons across a target protein family.
Sponsorship
Research Councils UK (BB/P50466X/1, EP/ L016044/1)
Wellcome Trust (106169/ZZ14/Z, 106169/Z/14/Z)
Innovative Medicines Initiative (115766, 875510)
Identifiers
PMC8790751, 35020376
External DOI: https://doi.org/10.1021/acs.jcim.1c00823
This record's URL: https://www.repository.cam.ac.uk/handle/1810/333967
Rights
Attribution-NonCommercial-NoDerivatives 4.0 International
Licence URL: https://creativecommons.org/licenses/by-nc-nd/4.0/
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