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Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains
The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allos...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995120/ https://www.ncbi.nlm.nih.gov/pubmed/36705568 http://dx.doi.org/10.7554/eLife.83602 |
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author | Meller, Artur Lotthammer, Jeffrey M Smith, Louis G Novak, Borna Lee, Lindsey A Kuhn, Catherine C Greenberg, Lina Leinwand, Leslie A Greenberg, Michael J Bowman, Gregory R |
author_facet | Meller, Artur Lotthammer, Jeffrey M Smith, Louis G Novak, Borna Lee, Lindsey A Kuhn, Catherine C Greenberg, Lina Leinwand, Leslie A Greenberg, Michael J Bowman, Gregory R |
author_sort | Meller, Artur |
collection | PubMed |
description | The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin’s binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R(2)=0.82). In a blind prediction for an isoform (Myh7b) whose blebbistatin sensitivity was unknown, we find good agreement between predicted and measured IC50s (0.67 μM vs. 0.36 μM). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets. |
format | Online Article Text |
id | pubmed-9995120 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-99951202023-03-09 Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains Meller, Artur Lotthammer, Jeffrey M Smith, Louis G Novak, Borna Lee, Lindsey A Kuhn, Catherine C Greenberg, Lina Leinwand, Leslie A Greenberg, Michael J Bowman, Gregory R eLife Computational and Systems Biology The design of compounds that can discriminate between closely related target proteins remains a central challenge in drug discovery. Specific therapeutics targeting the highly conserved myosin motor family are urgently needed as mutations in at least six of its members cause numerous diseases. Allosteric modulators, like the myosin-II inhibitor blebbistatin, are a promising means to achieve specificity. However, it remains unclear why blebbistatin inhibits myosin-II motors with different potencies given that it binds at a highly conserved pocket that is always closed in blebbistatin-free experimental structures. We hypothesized that the probability of pocket opening is an important determinant of the potency of compounds like blebbistatin. To test this hypothesis, we used Markov state models (MSMs) built from over 2 ms of aggregate molecular dynamics simulations with explicit solvent. We find that blebbistatin’s binding pocket readily opens in simulations of blebbistatin-sensitive myosin isoforms. Comparing these conformational ensembles reveals that the probability of pocket opening correctly identifies which isoforms are most sensitive to blebbistatin inhibition and that docking against MSMs quantitatively predicts blebbistatin binding affinities (R(2)=0.82). In a blind prediction for an isoform (Myh7b) whose blebbistatin sensitivity was unknown, we find good agreement between predicted and measured IC50s (0.67 μM vs. 0.36 μM). Therefore, we expect this framework to be useful for the development of novel specific drugs across numerous protein targets. eLife Sciences Publications, Ltd 2023-01-27 /pmc/articles/PMC9995120/ /pubmed/36705568 http://dx.doi.org/10.7554/eLife.83602 Text en © 2023, Meller et al https://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Computational and Systems Biology Meller, Artur Lotthammer, Jeffrey M Smith, Louis G Novak, Borna Lee, Lindsey A Kuhn, Catherine C Greenberg, Lina Leinwand, Leslie A Greenberg, Michael J Bowman, Gregory R Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title | Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title_full | Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title_fullStr | Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title_full_unstemmed | Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title_short | Drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
title_sort | drug specificity and affinity are encoded in the probability of cryptic pocket opening in myosin motor domains |
topic | Computational and Systems Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9995120/ https://www.ncbi.nlm.nih.gov/pubmed/36705568 http://dx.doi.org/10.7554/eLife.83602 |
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