1ym4
Crystal structure of human beta secretase complexed with NVP-AMK640
OverviewOverview
Molecular modeling based on the X-ray crystal structure of the Tang-Ghosh heptapeptide inhibitor 1 (OM99-2) of BACE led to the design and synthesis of a series of constrained P(1)' analogues. A cyclopentane ring was incorporated in 1 spanning the P(1)' Ala methyl group and the adjacent methylene carbon atom of the chain. Progressive truncation at the P(2)'-P(4)' sites led to a potent truncated analogue 5 with good selectivity over Cathepsin D. Using the same backbone replacement concept, a series of cyclopentane, cyclopentanone, tetrahydrofuran, pyrrolidine, and pyrrolidinone analogues were synthesized with considerable variation at the P and P' sites. The cyclopentanone and 2-pyrrolidinone analogues 45 and 57 showed low nM BACE inhibition. X-ray cocrystal structures of two analogues 5 and 45 revealed excellent convergence with the original inhibitor 1 structure while providing new insights into other interactions which could be exploited for future modifications.
About this StructureAbout this Structure
1YM4 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
ReferenceReference
Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics., Hanessian S, Yun H, Hou Y, Yang G, Bayrakdarian M, Therrien E, Moitessier N, Roggo S, Veenstra S, Tintelnot-Blomley M, Rondeau JM, Ostermeier C, Strauss A, Ramage P, Paganetti P, Neumann U, Betschart C, J Med Chem. 2005 Aug 11;48(16):5175-90. PMID:16078837 Page seeded by OCA on Sat May 3 16:29:56 2008