2f3e
From Proteopedia
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Crystal Structure of the Bace complex with AXQ093, a macrocyclic inhibitor
Overview
Based on the X-ray cocrystal structure of the Tang-Ghosh heptapeptide, inhibitor 1 (OM00-3), a series of macroheterocyclic analogues were, designed and synthesized. Analogues containing dithia, dioxa, oxathia, and, carbathia macrocycles were synthesized by methods relying on ring-closing, olefin metathesis for the dioxa analogues and by alkylation of thiolates, or bisthiolates for the others. Molecular modeling suggested that the, incorporation of piperidine units appended to the macrocycles improved, interactions through additional H-bonds and introduced further rigidity., These were synthesized in enantiomerically pure form using, enzyme-catalyzed desymmetrization and diastereomer separation. Inhibitory, activity on beta-site amyloid precursor protein cleaving enzyme (BACE) was, observed with several macroheterocyclic inhibitors and structure-activity, relationship (SAR) correlations were deduced. Cocrystal structures of two, synthetic analogues revealed interesting and unexpected binding, interactions.
About this Structure
2F3E is a Single protein structure of sequence from Homo sapiens with AXQ as ligand. Active as Memapsin 2, with EC number 3.4.23.46 Full crystallographic information is available from OCA.
Reference
Structure-based design and synthesis of macroheterocyclic peptidomimetic inhibitors of the aspartic protease beta-site amyloid precursor protein cleaving enzyme (BACE)., Hanessian S, Yang G, Rondeau JM, Neumann U, Betschart C, Tintelnot-Blomley M, J Med Chem. 2006 Jul 27;49(15):4544-67. PMID:16854060
Page seeded by OCA on Mon Nov 12 21:59:12 2007
