3V66

HUMAN SQUALENE SYNTHASE IN COMPLEX WITH 2-(1-{2-[(4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl}-4-piperidinyl)acetic acid

Summary for 3V66

• Entry DOI: 10.2210/pdb3v66/pdb
• Related: 3ASX 3Q2Z 3Q30
• Descriptor: Squalene synthase, PHOSPHATE ION, (1-{[(4R,6S)-8-chloro-6-(2,3-dimethoxyphenyl)-4H,6H-pyrrolo[1,2-a][4,1]benzoxazepin-4-yl]acetyl}piperidin-4-yl)acetic acid, ... (4 entities in total)
• Functional Keywords: terpenoid synthase fold, isoprene biosynthesis, lipid synthesis, multifunctional enzyme, oxidoreductase, steroid biosynthesis, sterol biosynthesis, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Endoplasmic reticulum membrane; Multi-pass membrane protein: P37268
• Total number of polymer chains: 1
• Total formula weight: 39800.69

Authors

Suzuki, M.,Ohtsuka, M.,Ohki, H.,Haginoya, N.,Itoh, M.,Sugita, K.,Usui, H.,Ichikawa, M.,Higashihashi, N. (deposition date: 2011-12-18, release date: 2012-12-19, Last modification date: 2023-11-08)

Primary citation

Ichikawa, M.,Ohtsuka, M.,Ohki, H.,Haginoya, N.,Itoh, M.,Sugita, K.,Usui, H.,Suzuki, M.,Terayama, K.,Kanda, A.
Discovery of novel tricyclic compounds as squalene synthase inhibitors
Bioorg.Med.Chem., 20:3072-3093, 2012

PubMed Abstract: In the present article, we have reported the design, synthesis, and identification of highly potent benzhydrol derivatives as squalene synthase inhibitors (compound 1). Unfortunately, the in vivo efficacies of the compounds were not enough for acquiring the clinical candidate. We continued our investigation to obtain a more in vivo efficacious template than the benzhydrol template. In our effort, we focused on a benzoxazepine ring and designed a new tricyclic scaffold by the incorporation of heterocycle into it. Prepared pyrrolobenzoxazepine derivatives showed further efficient in vitro and in vivo activities.

PubMed: 22464687
DOI: 10.1016/j.bmc.2012.02.054

Experimental method

X-RAY DIFFRACTION (1.8 Å)