Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase

Covalent kinase inhibitors (CKIs) have recently garnered considerable attention, yet the rational design of CKIs continues to pose a great challenge. In the discovery of CKIs targeting focal adhesion kinase (FAK), it has been observed that the chemical structure of the linkers plays a key role in ac...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2024-08, Vol.64 (15), p.6053-6061
Main Authors: Liu, Yiling, Tan, Jundong, Hu, Shiliang, Hussain, Muzammal, Qiao, Chang, Tu, Yaoquan, Lu, Xiaoyun, Zhou, Yang
Format: Article
Language:English
Subjects:
Adhesion
Computational Biochemistry
Covalence
Dynamic structural analysis
Kinases
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Summary:Covalent kinase inhibitors (CKIs) have recently garnered considerable attention, yet the rational design of CKIs continues to pose a great challenge. In the discovery of CKIs targeting focal adhesion kinase (FAK), it has been observed that the chemical structure of the linkers plays a key role in achieving covalent targeting of FAK. However, the mechanism behind the observation remains elusive. In this work, we employ a comprehensive suite of advanced computational methods to investigate the mechanism of CKIs covalently targeting FAK. We reveal that the linker of an inhibitor influences the contacts between the warhead and residue(s) and the residence time in active conformation, thereby dictating the inhibitor’s capability to bind covalently to FAK. This study reflects the complexity of CKI design and underscores the importance of considering the dynamic interactions and residence times for the successful development of covalent drugs.
ISSN:1549-9596
1549-960X
1549-960X
DOI:10.1021/acs.jcim.4c00418