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Title: Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity

Abstract

Gleevec is a potent inhibitor of Abl tyrosine kinase but not of the highly homologous c-Src kinase. Because the ligand binds to an inactive form of the protein in which an Asp-Phe-Gly structural motif along the activation loop adopts a so-called DFG-out conformation, it was suggested that binding specificity was controlled by a “conformational selection” mechanism. In this context, the binding affinity displayed by the kinase inhibitor G6G poses an intriguing challenge. Although it possesses a chemical core very similar to that of Gleevec, G6G is a potent inhibitor of both Abl and c-Src kinases. Both inhibitors bind to the DFG-out conformation of the kinases, which seems to be in contradiction with the conformational selection mechanism. To address this issue and display the hidden thermodynamic contributions affecting the binding selectivity, molecular dynamics free energy simulations with explicit solvent molecules were carried out. Relative to Gleevec, G6G forms highly favorable van der Waals dispersive interactions upon binding to the kinases via its triazine functional group, which is considerably larger than the corresponding pyridine moiety in Gleevec. Upon binding of G6G to c-Src, these interactions offset the unfavorable free energy cost of the DFG-out conformation. When binding to Abl, however, G6G experiencesmore » an unfavorable free energy penalty due to steric clashes with the phosphate-binding loop, yielding an overall binding affinity that is similar to that of Gleevec. Such steric clashes are absent when G6G binds to c-Src, due to the extended conformation of the phosphate-binding loop.« less

Authors:
 [1];  [1];  [1];  [1]
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  1. Univ. of Chicago, Chicago, IL (United States). Dept. of Biochemistry and Molecular Biology.
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Org.:
National Cancer Institute of the National Institutes of Health (NIH); National Science Foundation (NSF)
OSTI Identifier:
1214160
Grant/Contract Number:  
AC02-06CH11357
Resource Type:
Accepted Manuscript
Journal Name:
Journal of the American Chemical Society
Additional Journal Information:
Journal Volume: 136; Journal Issue: 42; Journal ID: ISSN 0002-7863
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Lin, Yen -Lin, Meng, Yilin, Huang, Lei, and Roux, Benoît. Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity. United States: N. p., 2014. Web. doi:10.1021/ja504146x.
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Lin, Yen -Lin, Meng, Yilin, Huang, Lei, & Roux, Benoît. Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity. United States. https://doi.org/10.1021/ja504146x
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Lin, Yen -Lin, Meng, Yilin, Huang, Lei, and Roux, Benoît. Wed . "Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity". United States. https://doi.org/10.1021/ja504146x. https://www.osti.gov/servlets/purl/1214160.
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@article{osti_1214160,
title = {Computational study of Gleevec and G6G reveals molecular determinants of kinase inhibitor selectivity},
author = {Lin, Yen -Lin and Meng, Yilin and Huang, Lei and Roux, Benoît},
abstractNote = {Gleevec is a potent inhibitor of Abl tyrosine kinase but not of the highly homologous c-Src kinase. Because the ligand binds to an inactive form of the protein in which an Asp-Phe-Gly structural motif along the activation loop adopts a so-called DFG-out conformation, it was suggested that binding specificity was controlled by a “conformational selection” mechanism. In this context, the binding affinity displayed by the kinase inhibitor G6G poses an intriguing challenge. Although it possesses a chemical core very similar to that of Gleevec, G6G is a potent inhibitor of both Abl and c-Src kinases. Both inhibitors bind to the DFG-out conformation of the kinases, which seems to be in contradiction with the conformational selection mechanism. To address this issue and display the hidden thermodynamic contributions affecting the binding selectivity, molecular dynamics free energy simulations with explicit solvent molecules were carried out. Relative to Gleevec, G6G forms highly favorable van der Waals dispersive interactions upon binding to the kinases via its triazine functional group, which is considerably larger than the corresponding pyridine moiety in Gleevec. Upon binding of G6G to c-Src, these interactions offset the unfavorable free energy cost of the DFG-out conformation. When binding to Abl, however, G6G experiences an unfavorable free energy penalty due to steric clashes with the phosphate-binding loop, yielding an overall binding affinity that is similar to that of Gleevec. Such steric clashes are absent when G6G binds to c-Src, due to the extended conformation of the phosphate-binding loop.},
doi = {10.1021/ja504146x},
journal = {Journal of the American Chemical Society},
number = 42,
volume = 136,
place = {United States},
year = {Wed Oct 22 00:00:00 EDT 2014},
month = {Wed Oct 22 00:00:00 EDT 2014}
}
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