School of Chemical and Environment Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
School of Chemical and Environment Engineering, Shanghai Institute of Technology, 100 Hai Quan Rd., Shanghai 201418, PR China.
Bioorg Med Chem. 2019 Apr 1;27(7):1382-1390. doi: 10.1016/j.bmc.2019.02.047. Epub 2019 Feb 22.
ROCK1 and ROCK2 are highly homologous isoforms. Accumulated studies indicate that they have distinct different functions, and the development of isoform selective ROCK inhibitors will pave new roads for the treatment of various diseases. In this work, a series of amide-chroman derivatives were synthesized and biologically evaluated in order to develop potent and isoform selective ROCK2 inhibitors. Remarkably, (S)-6-methoxy-chroman-3-carboxylic acid (4-pyridin-4-yl-phenyl)-amide ((S)-7c) possessed ROCK2 inhibitory activity with an IC value of 3 nM and 22.7-fold isoform selectivity (vs. ROCK1). Molecular docking indicated that hydrophobic interactions were the key element for the high potency and isoform selectivity of (S)-7c. The binding free energies predicted by MM/GBSA were in good agreement with the experimental bioactivities, and the analysis of individual energy terms suggested that residue Lys105 in ROCK1 or Lys121 in ROCK2 was the key residue for the isoform selectivity of (S)-7c.
ROCK1 和 ROCK2 是高度同源的同工型。积累的研究表明，它们具有明显不同的功能，开发同工型选择性 ROCK 抑制剂将为治疗各种疾病开辟新的道路。在这项工作中，我们合成了一系列酰胺色满衍生物，并对其进行了生物评价，以期开发出强效且同工型选择性的 ROCK2 抑制剂。值得注意的是，(S)-6-甲氧基色满-3-羧酸(4-吡啶-4-基-苯基)-酰胺((S)-7c)对 ROCK2 具有抑制活性，IC 值为 3nM，对 ROCK1 的同工型选择性为 22.7 倍。分子对接表明，疏水相互作用是 (S)-7c 高活性和同工型选择性的关键因素。通过 MM/GBSA 预测的结合自由能与实验生物活性吻合较好，对单个能量项的分析表明，ROCK1 中的残基 Lys105 或 ROCK2 中的残基 Lys121 是 (S)-7c 同工型选择性的关键残基。
