Identification of a Small Molecule Nonpeptide Active Site β-Secretase Inhibitor That Displays a Nontraditional Binding Mode for Aspartyl Proteases
Journal of Medicinal Chemistry2004Vol. 47(25), pp. 6117–6119
Citations Over TimeTop 10% of 2004 papers
Craig A. Coburn, Shawn J. Stachel, Yue‐Ming Li, Diane M. Rush, Thomas G. Steele, Elizabeth Chen-Dodson, M. Katharine Holloway, Min Xu, Qian Huang, Ming‐Tain Lai, Jillian DiMuzio, Ming‐Chih Crouthamel, Xiao‐Ping Shi, Vinod Sardana, Zhongguo Chen, Sanjeev Munshi, Lawrence Kuo, Gergely M. Makara, D. Allen Annis, Praveen K. Tadikonda, Huw M. Nash, Joseph P. Vacca, Tong Wang
Abstract
A small molecule nonpeptide inhibitor of beta-secretase has been developed, and its binding has been defined through crystallographic determination of the enzyme-inhibitor complex. The molecule is shown to bind to the catalytic aspartate residues in an unprecedented manner in the field of aspartyl protease inhibition. Additionally, the complex reveals a heretofore unknown S(3) subpocket that is created by the inhibitor. This structure has served an important role in the design of newer beta-secretase inhibitors.
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