State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
School of Management, Jinan University, Guangzhou 511400, China.
J Chem Inf Model. 2024 Aug 12;64(15):6053-6061. doi: 10.1021/acs.jcim.4c00418. Epub 2024 Jul 25.
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.
共价激酶抑制剂 (CKIs) 近来备受关注，但 CKIs 的合理设计仍然是一个巨大的挑战。在发现靶向黏着斑激酶 (FAK) 的 CKIs 时，人们观察到连接子的化学结构在实现 FAK 的共价靶向中起着关键作用。然而，这一观察结果背后的机制仍难以捉摸。在这项工作中，我们采用了一整套先进的计算方法来研究 CKIs 共价靶向 FAK 的机制。我们揭示了抑制剂的连接子会影响弹头与残基之间的接触以及在活性构象中的停留时间，从而决定了抑制剂与 FAK 共价结合的能力。这项研究反映了 CKI 设计的复杂性，并强调了考虑动态相互作用和停留时间对于成功开发共价药物的重要性。
