PAK Research Center, University of the Ryukyus, Okinawa, Japan.
Department of Bioscience and Biotechnology, University of the Ryukyus, Okinawa, Japan.
J Biomol Struct Dyn. 2020 Aug;38(12):3514-3526. doi: 10.1080/07391102.2019.1659855. Epub 2019 Sep 5.
The oncogenic kinase PAK1 (p21-activated kinase 1) is involved in developing many diseases including cancers, neurofibromatosis, Alzheimer's disease, diabetes (type 2), and hypertension. Thus, it is thought to be a prominent therapeutic target, and its selective inhibitors have a huge market potential. Recently, herbal PAK1 inhibitors have gained immense interest over synthetic ones mainly due to their non-toxic effects. Till date, many herbal compounds have been suggested to inhibit PAK1, but their information on selectivity, bioavailability, ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties, and molecular interactions with PAK1 has not been explored. Hence, this study was designed with computational approaches to explore and identify the best herbal PAK1-blockers showing good ADMET properties, druggable features and binding affinity with PAK1. Herbal inhibitors reported here were initially filtered with Lipinski's rule of five (RO5). Then, molecular docking between these inhibitors and PAK1 catalytic sites was performed using AutoDock Vina and GOLD suite to determine the binding affinity and interactions. Finally, 200 ns molecular dynamics (MD) simulations on three top-ranked inhibitors including cucurbitacin I (C-I), nymphaeol A (NA), and staurosporine (SPN) were carried out. The binding free energies and interactions revealed that NA can strongly bind with the PAK1 catalytic cleft. PASS prediction and ADMET profiling supported that NA is appeared to be a more selective and safer inhibitor than C-I and SPN. These results conform to the previous experimental evidences, and therefore, NA from Okinawa propolis could be a promising inhibitor for treating PAK1-dependent illnesses.Communicated by Ramaswamy H. Sarma.
致癌激酶 PAK1（p21 激活激酶 1）参与多种疾病的发展，包括癌症、神经纤维瘤病、阿尔茨海默病、糖尿病（2 型）和高血压。因此，它被认为是一个重要的治疗靶点，其选择性抑制剂具有巨大的市场潜力。最近，由于其无毒作用，草药 PAK1 抑制剂比合成抑制剂受到了极大的关注。迄今为止，已经有许多草药化合物被建议抑制 PAK1，但它们的选择性、生物利用度、ADMET（吸收、分布、代谢、排泄和毒性）特性以及与 PAK1 的分子相互作用的信息尚未得到探索。因此，本研究采用计算方法设计，以探索和识别具有良好 ADMET 特性、可成药性和与 PAK1 结合亲和力的最佳草药 PAK1 阻断剂。这里报告的草药抑制剂最初通过 Lipinski 的五规则（RO5）进行过滤。然后，使用 AutoDock Vina 和 GOLD 套件在这些抑制剂和 PAK1 催化位点之间进行分子对接，以确定结合亲和力和相互作用。最后，对三种排名靠前的抑制剂（包括苦瓜素 I（C-I）、水仙苷 A（NA）和星孢菌素（SPN））进行了 200ns 的分子动力学（MD）模拟。结合自由能和相互作用表明，NA 可以与 PAK1 的催化裂缝强烈结合。PASS 预测和 ADMET 分析支持 NA 比 C-I 和 SPN 更具选择性和安全性。这些结果与先前的实验证据一致，因此，来自冲绳蜂胶的 NA 可能是治疗 PAK1 依赖性疾病的有前途的抑制剂。由 Ramaswamy H. Sarma 传达。
