4fsl

Crystal structure of beta-site app-cleaving enzyme 1 (BACE-DB-MUT) complex with N-(N-(4- acetamido-3-chloro-5-methylbenzyl)carbamimidoyl)-3-(4- methoxyphenyl)-5-methyl-4-isothiazolecarboxamide

spinqualitylabelsall models 4fsl, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4fsl is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 0VB, IOD Related: 4fse Gene: BACE1, BACE, KIAA1149 (HUMAN) Activity: Memapsin 2, with EC number 3.4.23.46 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [BACE1_HUMAN] Responsible for the proteolytic processing of the amyloid precursor protein (APP). Cleaves at the N-terminus of the A-beta peptide sequence, between residues 671 and 672 of APP, leads to the generation and extracellular release of beta-cleaved soluble APP, and a corresponding cell-associated C-terminal fragment which is later released by gamma-secretase. Publication Abstract from PubMed This report describes the discovery and optimization of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma Abeta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain Abeta levels were not obtained. Acyl guanidine inhibitors of beta-secretase (BACE-1): optimization of a micromolar hit to a nanomolar lead via iterative solid- and solution-phase library synthesis.,Gerritz SW, Zhai W, Shi S, Zhu S, Toyn JH, Meredith JE Jr, Iben LG, Burton CR, Albright CF, Good AC, Tebben AJ, Muckelbauer JK, Camac DM, Metzler W, Cook LS, Padmanabha R, Lentz KA, Sofia MJ, Poss MA, Macor JE, Thompson LA 3rd J Med Chem. 2012 Nov 8;55(21):9208-23. doi: 10.1021/jm300931y. Epub 2012 Oct 2. PMID:23030502 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase

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