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How does a small molecule bind at a cryptic binding site?

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPI...

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Autores principales: Shan, Yibing, Mysore, Venkatesh P., Leffler, Abba E., Kim, Eric T., Sagawa, Shiori, Shaw, David E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893328/
https://www.ncbi.nlm.nih.gov/pubmed/35239648
http://dx.doi.org/10.1371/journal.pcbi.1009817
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author Shan, Yibing
Mysore, Venkatesh P.
Leffler, Abba E.
Kim, Eric T.
Sagawa, Shiori
Shaw, David E.
author_facet Shan, Yibing
Mysore, Venkatesh P.
Leffler, Abba E.
Kim, Eric T.
Sagawa, Shiori
Shaw, David E.
author_sort Shan, Yibing
collection PubMed
description Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are “cryptic”: When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)—which performs its function by forming a PPI with its receptor—without incorporating any prior structural information about the ligands’ binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein–small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2–small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.
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spelling pubmed-88933282022-03-04 How does a small molecule bind at a cryptic binding site? Shan, Yibing Mysore, Venkatesh P. Leffler, Abba E. Kim, Eric T. Sagawa, Shiori Shaw, David E. PLoS Comput Biol Research Article Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are “cryptic”: When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)—which performs its function by forming a PPI with its receptor—without incorporating any prior structural information about the ligands’ binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein–small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2–small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites. Public Library of Science 2022-03-03 /pmc/articles/PMC8893328/ /pubmed/35239648 http://dx.doi.org/10.1371/journal.pcbi.1009817 Text en © 2022 Shan et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Shan, Yibing
Mysore, Venkatesh P.
Leffler, Abba E.
Kim, Eric T.
Sagawa, Shiori
Shaw, David E.
How does a small molecule bind at a cryptic binding site?
title How does a small molecule bind at a cryptic binding site?
title_full How does a small molecule bind at a cryptic binding site?
title_fullStr How does a small molecule bind at a cryptic binding site?
title_full_unstemmed How does a small molecule bind at a cryptic binding site?
title_short How does a small molecule bind at a cryptic binding site?
title_sort how does a small molecule bind at a cryptic binding site?
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8893328/
https://www.ncbi.nlm.nih.gov/pubmed/35239648
http://dx.doi.org/10.1371/journal.pcbi.1009817
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