4x2l | pdb_00004x2l

Crystal structure of human BACE-1 bound to Compound 6

spinqualitylabelsall models 4x2l, resolution 2.55Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4x2l is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3WP, DMS, GOL, IOD, NA 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 The identification of centrally efficacious beta-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired ADME properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective in garnering BACE1 activity without simultaneously inhibiting the closely related Cathepsin D or negatively impacting brain penetration and ADME alignment, as exemplified by 36. Oral administration of these inhibitors exhibit robust brain availability and are efficacious in lowering central Abeta levels in mouse and dog. In addition, chronic treatment in aged PS1/APP mice effects a decrease in the number and size of Abeta-derived plaques. Most importantly, evaluation of 36 in a two-week exploratory toxicology study revealed no accumulation of autofluorescent material in retinal pigment epithelium or histology findings in the eye, issues observed with earlier BACE1 inhibitors. Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design.,Butler CR, Brodney MA, Beck EM, Barreiro G, Nolan CE, Pan F, Vajdos FF, Parris K, Varghese AH, Helal CJ, Lira R, Doran SD, Riddell D, Buzon LM, Dutra JK, Martinez-Alsina LA, Ogilvie K, Murray JC, Young JM, Atchison K, Robshaw A, Gonzales C, Wang J, Zhang Y, O'Neill BT J Med Chem. 2015 Feb 19. PMID:25695670 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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