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Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases
[Image: see text] Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10685456/ https://www.ncbi.nlm.nih.gov/pubmed/37948537 http://dx.doi.org/10.1021/acs.jcim.3c01469 |
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author | Champion, Candide Gall, René Ries, Benjamin Rieder, Salomé R. Barros, Emilia P. Riniker, Sereina |
author_facet | Champion, Candide Gall, René Ries, Benjamin Rieder, Salomé R. Barros, Emilia P. Riniker, Sereina |
author_sort | Champion, Candide |
collection | PubMed |
description | [Image: see text] Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods to rank potential binders from best to worst is impacted by the combinatorial increase in calculations to perform when the number of molecules to assess grows. To address this fundamental limitation, our group has developed replica-exchange enveloping distribution sampling (RE-EDS), a pathway-independent multistate method, enabling the calculation of alchemical free-energy differences between multiple ligands (N > 2) from a single MD simulation. In this work, we apply the method to a set of four kinases with diverse binding pockets and their corresponding inhibitors (42 in total), chosen to showcase the general applicability of RE-EDS in prospective drug design campaigns. We show that for the targets studied, RE-EDS is able to model up to 13 ligands simultaneously with high sampling efficiency, leading to a substantial decrease in computational cost when compared to pairwise methods. |
format | Online Article Text |
id | pubmed-10685456 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-106854562023-11-30 Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases Champion, Candide Gall, René Ries, Benjamin Rieder, Salomé R. Barros, Emilia P. Riniker, Sereina J Chem Inf Model [Image: see text] Alchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods to rank potential binders from best to worst is impacted by the combinatorial increase in calculations to perform when the number of molecules to assess grows. To address this fundamental limitation, our group has developed replica-exchange enveloping distribution sampling (RE-EDS), a pathway-independent multistate method, enabling the calculation of alchemical free-energy differences between multiple ligands (N > 2) from a single MD simulation. In this work, we apply the method to a set of four kinases with diverse binding pockets and their corresponding inhibitors (42 in total), chosen to showcase the general applicability of RE-EDS in prospective drug design campaigns. We show that for the targets studied, RE-EDS is able to model up to 13 ligands simultaneously with high sampling efficiency, leading to a substantial decrease in computational cost when compared to pairwise methods. American Chemical Society 2023-11-10 /pmc/articles/PMC10685456/ /pubmed/37948537 http://dx.doi.org/10.1021/acs.jcim.3c01469 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by-nc-nd/4.0/Permits non-commercial access and re-use, provided that author attribution and integrity are maintained; but does not permit creation of adaptations or other derivative works (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Champion, Candide Gall, René Ries, Benjamin Rieder, Salomé R. Barros, Emilia P. Riniker, Sereina Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases |
title | Accelerating Alchemical
Free Energy Prediction Using
a Multistate Method: Application to Multiple Kinases |
title_full | Accelerating Alchemical
Free Energy Prediction Using
a Multistate Method: Application to Multiple Kinases |
title_fullStr | Accelerating Alchemical
Free Energy Prediction Using
a Multistate Method: Application to Multiple Kinases |
title_full_unstemmed | Accelerating Alchemical
Free Energy Prediction Using
a Multistate Method: Application to Multiple Kinases |
title_short | Accelerating Alchemical
Free Energy Prediction Using
a Multistate Method: Application to Multiple Kinases |
title_sort | accelerating alchemical
free energy prediction using
a multistate method: application to multiple kinases |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10685456/ https://www.ncbi.nlm.nih.gov/pubmed/37948537 http://dx.doi.org/10.1021/acs.jcim.3c01469 |
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