4wy6

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Crystal structure of human BACE-1 bound to Compound 36

Structural highlights

4wy6 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 2.1Å
Ligands:3VP, DMS, IOD
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.[1] [2]

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[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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See Also

References

  1. Lin X, Koelsch G, Wu S, Downs D, Dashti A, Tang J. Human aspartic protease memapsin 2 cleaves the beta-secretase site of beta-amyloid precursor protein. Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1456-60. PMID:10677483
  2. Okada H, Zhang W, Peterhoff C, Hwang JC, Nixon RA, Ryu SH, Kim TW. Proteomic identification of sorting nexin 6 as a negative regulator of BACE1-mediated APP processing. FASEB J. 2010 Aug;24(8):2783-94. doi: 10.1096/fj.09-146357. Epub 2010 Mar 30. PMID:20354142 doi:10.1096/fj.09-146357
  3. 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. Discovery of a Series of Efficient, Centrally Efficacious BACE1 Inhibitors through Structure-Based Drug Design. J Med Chem. 2015 Feb 19. PMID:25695670 doi:http://dx.doi.org/10.1021/jm501833t

Contents


PDB ID 4wy6

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