3vv8 | pdb_00003vv8

Crystal structure of beta secetase in complex with 2-amino-3-methyl-6-((1S,2R)-2-(3'-methylbiphenyl-4-yl)cyclopropyl)pyrimidin-4(3H)-one

spinqualitylabelsall models 3vv8, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3vv8 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.5Å Ligands: B02, GOL Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Improvement of a drug's binding activity using the conformational restriction approach with sp(3) hybridized carbon is becoming a key strategy in drug discovery. We applied this approach to BACE1 inhibitors and designed four stereoisomeric cyclopropane compounds in which the ethylene linker of a known amidine-type inhibitor 2 was replaced with chiral cyclopropane rings. The synthesis and biologic evaluation of these compounds revealed that the cis-(1S,2R) isomer 6 exhibited the most potent BACE1 inhibitory activity among them. X-ray structure analysis of the complex of 6 and BACE1 revealed that its unique binding mode is due to the apparent CH-pi interaction between the rigid cyclopropane ring and the Tyr71 side chain. A derivatization study using 6 as a lead molecule led to the development of highly potent inhibitors in which the structure-activity relationship as well as the binding mode of the compounds clearly differ from those of known amidine-type inhibitors. Conformational Restriction Approach to beta-Secretase (BACE1) Inhibitors: Effect of a Cyclopropane Ring To Induce an Alternative Binding Mode.,Yonezawa S, Yamamoto T, Yamakawa H, Muto C, Hosono M, Hattori K, Higashino K, Yutsudo T, Iwamoto H, Kondo Y, Sakagami M, Togame H, Tanaka Y, Nakano T, Takemoto H, Arisawa M, Shuto S J Med Chem. 2012 Oct 8. PMID:22998419 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase 3D structures

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