Takami Atsuya, Iwakubo Masayuki, Okada Yuji, Kawata Takehisa, Odai Hideharu, Takahashi Nobuaki, Shindo Kazutoshi, Kimura Kaname, Tagami Yoshimichi, Miyake Mika, Fukushima Kayoko, Inagaki Masaki, Amano Mutsuki, Kaibuchi Kozo, Iijima Hiroshi
Pharmaceutical Research Laboratories, Kirin Brewery Co. Ltd, 3 Miyhara-cho, Takasaki-shi, Gunma 370-1295, Japan.
Bioorg Med Chem. 2004 May 1;12(9):2115-37. doi: 10.1016/j.bmc.2004.02.025.
Several structurally unrelated scaffolds of the Rho kinase inhibitor were designed using pharmacophore information obtained from the results of a high-throughput screening and structural information from a homology model of Rho kinase. A docking simulation using the ligand-binding pocket of the Rho kinase model helped to comprehensively understand and to predict the structure-activity relationship of the inhibitors. This understanding was useful for developing new Rho kinase inhibitors of higher potency and selectivity. We identified several potent platforms for developing the Rho kinase inhibitors, namely, pyridine, 1H-indazole, isoquinoline, and phthalimide.
利用高通量筛选结果获得的药效团信息以及Rho激酶同源模型的结构信息，设计了几种结构不相关的Rho激酶抑制剂支架。使用Rho激酶模型的配体结合口袋进行对接模拟，有助于全面理解和预测抑制剂的构效关系。这种理解对于开发更高效和更具选择性的新型Rho激酶抑制剂很有用。我们确定了几种开发Rho激酶抑制剂的有效平台，即吡啶、1H-吲唑、异喹啉和邻苯二甲酰亚胺。
