| Literature DB >> 18811140 |
James C Barrow1, Shaun R Stauffer, Kenneth E Rittle, Phung L Ngo, ZhiQiang Yang, Harold G Selnick, Samuel L Graham, Sanjeev Munshi, Georgia B McGaughey, M Katharine Holloway, Adam J Simon, Eric A Price, Sethu Sankaranarayanan, Dennis Colussi, Katherine Tugusheva, Ming-Tain Lai, Amy S Espeseth, Min Xu, Qian Huang, Abigail Wolfe, Beth Pietrak, Paul Zuck, Dorothy A Levorse, Daria Hazuda, Joseph P Vacca.
Abstract
A high-throughput screen at 100 microM inhibitor concentration for the BACE-1 enzyme revealed a novel spiropiperidine iminohydantoin aspartyl protease inhibitor template. An X-ray cocrystal structure with BACE-1 revealed a novel mode of binding whereby the inhibitor interacts with the catalytic aspartates via bridging water molecules. Using the crystal structure as a guide, potent compounds with good brain penetration were designed.Entities:
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Year: 2008 PMID： 18811140 DOI： 10.1021/jm800914n
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446