3in4 | pdb_00003in4

Bace1 with Compound 38

spinqualitylabelsall models 3in4, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3in4 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. Ligands: BX2 Related: 3in3 Gene: BACE1, BACE, KIAA1149 (Homo sapiens) Activity: Memapsin 2, with EC number 3.4.23.46 Resources: FirstGlance, OCA, RCSB, PDBsum 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 PubMed The identification of highly selective small molecule di-substituted pyridinyl aminohydantoins as beta-secretase inhibitors is reported. The more potent and selective analogs demonstrate low nanomolar potency for the BACE1 enzyme as measured in a FRET assay, and exhibit comparable activity in a cell-based (ELISA) assay. In addition, these pyridine-aminohydantoins are highly selectivity (>500x) against the other structurally related aspartyl proteases BACE2, cathepsin D, pepsin and renin. Our design strategy followed a traditional SAR approach and was supported by molecular modeling studies based on the previously reported aminohydantoin 3a. We have taken advantage of the amino acid difference between the BACE1 and BACE2 at the S2' pocket (BACE1 Pro(70) changed to BACE2 Lys(86)) to build ligands with >500-fold selectivity against BACE2. The addition of large substituents on the targeted ligand at the vicinity of this aberration has generated a steric conflict between the ligand and these two proteins, thus impacting the ligand's affinity and selectivity. These ligands have also shown an exceptional selectivity against cathepsin D (>5000-fold) as well as the other aspartyl proteases mentioned. One of the more potent compounds (S)-39 displayed an IC(50) value for BACE1 of 10nM, and exhibited cellular activity with an EC(50) value of 130nM in the ELISA assay. Di-substituted pyridinyl aminohydantoins as potent and highly selective human beta-secretase (BACE1) inhibitors.,Malamas MS, Barnes K, Johnson M, Hui Y, Zhou P, Turner J, Hu Y, Wagner E, Fan K, Chopra R, Olland A, Bard J, Pangalos M, Reinhart P, Robichaud AJ Bioorg Med Chem. 2010 Jan 15;18(2):630-9. Epub 2009 Dec 6. PMID:20045648 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta secretase

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