1ym4
Crystal structure of human beta secretase complexed with NVP-AMK640Crystal structure of human beta secretase complexed with NVP-AMK640
Structural highlights
Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedMolecular 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. 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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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