1. Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase.
- Author
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Liu Y, Tan J, Hu S, Hussain M, Qiao C, Tu Y, Lu X, and Zhou Y
- Subjects
- Protein Conformation, Humans, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors metabolism, Focal Adhesion Protein-Tyrosine Kinases antagonists & inhibitors, Focal Adhesion Protein-Tyrosine Kinases metabolism, Focal Adhesion Protein-Tyrosine Kinases chemistry, Protein Binding, Molecular Dynamics Simulation
- Abstract
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.
- Published
- 2024
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