Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton's Tyrosine Kinase via Molecular Dynamics Simulations.
Comparison of Intermolecular Interactions of Irreversible and Reversible Inhibitors with Bruton's Tyrosine Kinase via Molecular Dynamics Simulations.
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通过分子动力学模拟比较不可逆和可逆抑制剂与布鲁顿酪氨酸激酶的分子间相互作用
DOI：
10.3390/molecules27217451
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发表时间：
2022-11-02
期刊：
影响因子：
--
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Yu X;Qiu S;Sun D;Guo P;Li Q
布鲁顿酪氨酸激酶（BTK）是TEC家族的一种关键蛋白，参与B细胞淋巴瘤的发生和发展。因此，靶向BTK是治疗B细胞淋巴瘤的一种有效策略。由于先前对BTK的研究仅限于静态蛋白质结构的结构 - 功能分析，BTK在抑制剂结合时构象变化的动态过程仍不清楚。在此，进行了分子动力学模拟以研究可逆（ARQ531）和不可逆（依鲁替尼）小分子抑制剂与BTK结合及解离的分子机制。结果表明，发现BTK激酶结构域通过DFG基序以及P - 、A - 和守门员环的局部构象变化被锁定在无活性状态。抑制剂的结合促使C - 螺旋向外旋转，导致色氨酸395向上折叠以及谷氨酸445 - 精氨酸544盐桥的形成，从而维持无活性构象状态。铰链区的蛋氨酸477和谷氨酸475被发现是抑制剂结合的关键残基。这些发现可用于评估药效团的抑制活性，并应用于有效BTK抑制剂的设计。此外，对不可逆抑制剂依鲁替尼的耐药性主要源于半胱氨酸481的强相互作用，这通过突变实验得到证明，并通过导向分子动力学模拟对破裂力和破裂次数的测量进一步得到证实。我们的结果为针对BTK靶向药物的耐药性以及开发高质量BTK抑制剂的关键相互作用位点提供了机制方面的见解。导向动力学模拟也提供了一种快速评估新设计抑制剂结合能力的方法。
Bruton’s tyrosine kinase (BTK) is a key protein from the TEC family and is involved in B-cell lymphoma occurrence and development. Targeting BTK is therefore an effective strategy for B-cell lymphoma treatment. Since previous studies on BTK have been limited to structure-function analyses of static protein structures, the dynamics of conformational change of BTK upon inhibitor binding remain unclear. Here, molecular dynamics simulations were conducted to investigate the molecular mechanisms of association and dissociation of a reversible (ARQ531) and irreversible (ibrutinib) small-molecule inhibitor to/from BTK. The results indicated that the BTK kinase domain was found to be locked in an inactive state through local conformational changes in the DFG motif, and P-, A-, and gatekeeper loops. The binding of the inhibitors drove the outward rotation of the C-helix, resulting in the upfolded state of Trp395 and the formation of the salt bridge of Glu445-Arg544, which maintained the inactive conformation state. Met477 and Glu475 in the hinge region were found to be the key residues for inhibitor binding. These findings can be used to evaluate the inhibitory activity of the pharmacophore and applied to the design of effective BTK inhibitors. In addition, the drug resistance to the irreversible inhibitor Ibrutinib was mainly from the strong interaction of Cys481, which was evidenced by the mutational experiment, and further confirmed by the measurement of rupture force and rupture times from steered molecular dynamics simulation. Our results provide mechanistic insights into resistance against BTK-targeting drugs and the key interaction sites for the development of high-quality BTK inhibitors. The steered dynamics simulation also offers a means to rapidly assess the binding capacity of newly designed inhibitors.
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影响因子：
2.2
作者：
Goess, Christian;Harris, Christopher M.;Long, Andrew J.
通讯作者：
Long, Andrew J.
DOI：
10.1007/978-1-4939-7000-1_26
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Burley SK;Berman HM;Kleywegt GJ;Markley JL;Nakamura H;Velankar S
通讯作者：
Velankar S
DOI：
10.1124/jpet.113.203489
发表时间：
2013-08-01
影响因子：
3.5
作者：
Evans, Erica K.;Tester, Richland;Westlin, William F.
通讯作者：
Westlin, William F.
非共价抑制剂 XMU-MP-3 可以克服 B 细胞恶性肿瘤中的依鲁替尼耐药 Btk(C481S) 突变
影响因子：
7.3
作者：
Gui, Fu;Jiang, Jie;Deng, Xianming
通讯作者：
Deng, Xianming
影响因子：
20.3
作者：
Jebaraj, Billy Michael Chelliah;Mueller, Annika;Stilgenbauer, Stephan
通讯作者：
Stilgenbauer, Stephan