Kumar Pawan, Khan Rajni, Singh Basant Narain, Kumari Anisha, Rai Ankit, Singh Anil Kumar, Prakash Amresh, Ray Shashikant
School of Computational and Integrative Sciences, Jawaharlal Nehru University, New Delhi, Delhi, 110067, India.
Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Hajipur, 844102, India.
Sci Rep. 2024 Dec 28;14(1):31381. doi: 10.1038/s41598-024-82823-8.
Microtubules are dynamic cytoskeletal structures essential for cell architecture, cellular transport, cell motility, and cell division. Due to their dynamic nature, known as dynamic instability, microtubules can spontaneously switch between phases of growth and shortening. Disruptions in microtubule functions have been implicated in several diseases, including cancer, neurodegenerative disorders such as Alzheimer's and Parkinson's disease, and birth defects. The role of microtubules during various phases of the cell cycle, particularly in cell division, makes them attractive targets for drug development against cancer. Several successful drugs currently on the market are designed to target microtubules. However, the presence of cellular toxicity and the development of multidrug resistance necessitate the search for new microtubule-targeting drugs.Here, a library of 106 biologically active compounds were screened to identify potent microtubule assembly inhibitors. Out of all the screened compounds, the hydroxyethylamine (HEA) analogues are found to be the best hit.We identified three inhibitors, BKS3031A, BKS3045A and BKS3046A, that bind at the same site as the well-known microtubule targeting agent colchicine. These inhibitors were simulated for 100 ns with tubulin complexes, and the results indicated that they remain stable within the binding pocket of α-β tubulin complexes. In addition, we estimated the binding free energy of BKS3031A, BKS3045A and BKS3046A by using molecular mechanics generalized Born surface area (MM-GBSA) calculations, and it was found to be -32.67 ± 6.01, -21.77 ± 5.12 and - 22.92 ± 5.09 kcal/mol, respectively. Our findings suggest that these novel inhibitors have potential to bind and perturb the microtubule network, positioning them as promising microtubule-targeting agents.
微管是细胞骨架的动态结构，对细胞结构、细胞运输、细胞运动和细胞分裂至关重要。由于其动态特性，即所谓的动态不稳定性，微管可以在生长和缩短阶段之间自发切换。微管功能的破坏与多种疾病有关，包括癌症、神经退行性疾病如阿尔茨海默病和帕金森病以及出生缺陷。微管在细胞周期的各个阶段，特别是在细胞分裂中的作用，使其成为抗癌药物开发的有吸引力的靶点。目前市场上有几种成功的药物就是设计用于靶向微管的。然而，细胞毒性的存在和多药耐药性的发展使得有必要寻找新的微管靶向药物。在此，对106种生物活性化合物库进行了筛选，以鉴定有效的微管组装抑制剂。在所有筛选的化合物中，羟乙胺（HEA）类似物被发现是最佳的命中物。我们鉴定出三种抑制剂，BKS3031A、BKS3045A和BKS3046A，它们与著名的微管靶向剂秋水仙碱结合在同一位置。这些抑制剂与微管蛋白复合物进行了100纳秒的模拟，结果表明它们在α-β微管蛋白复合物的结合口袋内保持稳定。此外，我们使用分子力学广义玻恩表面积（MM-GBSA）计算估计了BKS3031A、BKS3045A和BKS3046A的结合自由能，发现分别为-32.67±6.01、-21.77±5.12和-22.92±5.09千卡/摩尔。我们的研究结果表明，这些新型抑制剂有潜力结合并扰乱微管网络，使其成为有前景的微管靶向剂。
