School of Chemical Sciences, University of Chinese Academy of Sciences, No. 19A, YuQuan Road, Beijing 100049, PR China.
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA 23298, USA.
Future Med Chem. 2020 Mar;12(5):367-385. doi: 10.4155/fmc-2019-0273. Epub 2020 Feb 17.
The p21-activated kinases (PAKs) are involved in many important biological activity regulations. FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 were identified as PAKs inhibitors. Their detailed inhibitory mechanisms deserve further investigation. Molecular dynamics simulations and further calculations for the PAK1/inhibitor and PAK4/inhibitor complexes indicate that their binding free energies are basically consistent with the trend of experimental activity data. The anchoring of residues Leu347 and Leu398 is the structural basis for designing Afraxis PAK inhibitors. This study discloses the inhibitory mechanisms of FRAX019, FRAX414, FRAX597, FRAX1036 and G-5555 toward PAK1 and PAK4 and some clues to enhance kinase activities and selectivities, which will provide valuable information to the development of more potent and selective PAK inhibitors.
p21 激活激酶（PAKs）参与许多重要的生物活性调节。FRAX019、FRAX414、FRAX597、FRAX1036 和 G-5555 被鉴定为 PAK 抑制剂。它们的详细抑制机制值得进一步研究。PAK1/抑制剂和 PAK4/抑制剂复合物的分子动力学模拟和进一步计算表明，它们的结合自由能基本与实验活性数据的趋势一致。残基 Leu347 和 Leu398 的锚定是设计 Afraxis PAK 抑制剂的结构基础。本研究揭示了 FRAX019、FRAX414、FRAX597、FRAX1036 和 G-5555 对 PAK1 和 PAK4 的抑制机制，以及增强激酶活性和选择性的一些线索，这将为开发更有效和选择性的 PAK 抑制剂提供有价值的信息。
