Protein Flexibility and Dissociation Pathway Differentiation Can Explain Onset of Resistance Mutations in Kinases.
Kinase
Kinetics
Molecular Dynamics
Protein Flexibility
Resistance Mutations
Journal
Angewandte Chemie (International ed. in English)
ISSN: 1521-3773
Titre abrégé: Angew Chem Int Ed Engl
Pays: Germany
ID NLM: 0370543
Informations de publication
Date de publication:
11 07 2022
11 07 2022
Historique:
received:
19
01
2022
pubmed:
30
4
2022
medline:
7
7
2022
entrez:
29
4
2022
Statut:
ppublish
Résumé
Understanding how mutations render a drug ineffective is a problem of immense relevance. Often the mechanism through which mutations cause drug resistance can be explained purely through thermodynamics. However, the more perplexing situation is when two proteins have the same drug binding affinities but different residence times. In this work, we demonstrate how all-atom molecular dynamics simulations using recent developments grounded in statistical mechanics can provide a detailed mechanistic rationale for such variances. We discover dissociation mechanisms for the anti-cancer drug Imatinib (Gleevec) against wild-type and the N368S mutant of Abl kinase. We show how this point mutation triggers far-reaching changes in the protein's flexibility and leads to a different, much faster, drug dissociation pathway. We believe that this work marks an efficient and scalable approach to obtain mechanistic insight into resistance mutations in biomolecular receptors that are hard to explain using a structural perspective.
Identifiants
pubmed: 35486370
doi: 10.1002/anie.202200983
pmc: PMC9256798
mid: NIHMS1803513
doi:
Substances chimiques
Benzamides
0
Piperazines
0
Protein Kinase Inhibitors
0
Pyrimidines
0
Imatinib Mesylate
8A1O1M485B
Fusion Proteins, bcr-abl
EC 2.7.10.2
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202200983Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM119437
Pays : United States
Organisme : NIH HHS
ID : S10 OD028478
Pays : United States
Informations de copyright
© 2022 Wiley-VCH GmbH.
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