Bozdaganyan Marine, Fedorov Vladimir, Kholina Ekaterina, Kovalenko Ilya, Gudimchuk Nikita, Orekhov Philipp
Faculty of Biology, Shenzhen MSU-BIT University, Shenzhen, 518172, China.
Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
Sci Rep. 2025 Mar 11;15(1):8378. doi: 10.1038/s41598-025-92805-z.
Cancer treatment remains a pressing challenge, with paclitaxel playing a pivotal role in chemotherapy by disrupting mitotic spindle dynamics through microtubule stabilization. However, the molecular details of paclitaxel interaction with β-tubulin, its target, remain elusive, impeding efforts to overcome drug resistance and optimize efficacy. Here, we employ extensive molecular dynamics simulations to probe the binding modes of paclitaxel within tubulin protofilaments. Our simulations reveal a spectrum of paclitaxel binding poses, correlated with conformational changes in neighboring residues, proposing the ligand (un)binding route. These diverse binding modes exhibit varied interaction patterns and binding energies, elucidating the complex interplay between paclitaxel-tubulin interactions and the conformational dynamics of the M-loop. Furthermore, key residues influencing paclitaxel affinity and resistance are identified, enhancing our mechanistic understanding of the drug-binding mechanism. Finally, we uncover a novel high-affinity binding mode characterized by paclitaxel penetration into a subpocket formed by helices 1, 7, and loop B9-B10 of β-tubulin concerted with the rotational isomerization around a bond connecting the tetracyclic baccatin core with the N-benzoyl-β-phenylisoserine side chain, offering potential avenues for drug development. Our study advances the understanding of paclitaxel mode of action and informs strategies for rational drug design of antitumor agents.
癌症治疗仍然是一项紧迫的挑战，紫杉醇通过微管稳定作用破坏有丝分裂纺锤体动力学，在化疗中发挥着关键作用。然而，紫杉醇与其靶标β-微管蛋白相互作用的分子细节仍然难以捉摸，这阻碍了克服耐药性和优化疗效的努力。在这里，我们采用广泛的分子动力学模拟来探究紫杉醇在微管原丝中的结合模式。我们的模拟揭示了一系列紫杉醇的结合姿势，与相邻残基的构象变化相关，提出了配体（解）结合途径。这些不同的结合模式表现出不同的相互作用模式和结合能，阐明了紫杉醇-微管蛋白相互作用与M环构象动力学之间的复杂相互作用。此外，确定了影响紫杉醇亲和力和耐药性的关键残基，增强了我们对药物结合机制的机理理解。最后，我们发现了一种新的高亲和力结合模式，其特征是紫杉醇渗透到由β-微管蛋白的螺旋1、7和环B9-B10形成的亚口袋中，同时围绕连接四环巴卡亭核心与N-苯甲酰基-β-苯基异丝氨酸侧链的键发生旋转异构化，为药物开发提供了潜在途径。我们的研究推进了对紫杉醇作用模式的理解，并为抗肿瘤药物的合理设计提供了策略。
