共查询到20条相似文献,搜索用时 31 毫秒
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Yutaka Mori Yasuyuki Ogawa Akiyoshi Mochizuki Yuji Nakamura Teppei Fujimoto Chie Sugita Shojiro Miyazaki Kazuhiko Tamaki Takahiro Nagayama Yoko Nagai Shin-ichi Inoue Katsuyoshi Chiba Takahide Nishi 《Bioorganic & medicinal chemistry》2013,21(18):5907-5922
We report synthesis and optimization of a series of (3S,5R)-5-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)piperidine-3-carboxamides as renin inhibitors. Chemical modification of , and P3 portions led to a promising 3,5-disubstituted piperidine 32o showing high renin inhibitory activity and favorable oral exposure in both rats and cynomolgus monkeys with acceptable CYP and hERG current inhibition. Compound 32o exhibited a significant blood pressure lowering effect by oral administration in two hypertensive animal models, double transgenic rats and furosemide pretreated cynomolgus monkeys. 相似文献
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《Bio Systems》2009,95(3):233-241
A computer study of the prediction of the protein crystal’s shape and polymorphism of crystal’s structures within the limits resulting from the exploration of the Miyazawa–Jernigan matrix is presented. In this study, a coarse-graining procedure was applied to prepare a two-dimensional growth unit, where instead of full atom representation of the protein a two-type (hydrophobic–hydrophilic, HP) aminoacidal representation was used. The interaction energies between hydrophobic () aminoacids were chosen from the well-known HP-type models (), whereas interaction energies between hydrophobic and hydrophilic aminoacids () as well as interaction energies between hydrophilic aminoacids () were chosen from the range: , but not all values from this range fulfiled limitations resulting from the exploration of the Miyazawa–Jernigan matrix. Exploring every positively vetted combinations of energy interactions a polymorphism of the unit cell was observed what led to the fact that different final crystal’s shapes were obtained. 相似文献
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Naohiro Nishikawa Yoshitake Sakae Takuya Gouda Yuichiro Tsujimura Yuko Okamoto 《Biophysical journal》2019,116(5):781-790
A peptide -, which is a fragment from residue 21 to residue 31 of -microgloblin, is experimentally known to self-assemble and form amyloid fibrils. In order to understand the mechanism of amyloid fibril formations, we applied the replica-exchange molecular dynamics method to the system consisting of three fragments of -. From the analyses on the temperature dependence, we found that there is a clear phase transition temperature in which the peptides aggregate with each other. Moreover, we found by the free energy analyses that there are two major stable states: One of them is like amyloid fibrils and the other is amorphous aggregates. 相似文献
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