Therapeutic Targets Database
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TTD Target ID: TTDC00092

Target Information
NameBeta-secretase    
Type of targetClinical trial target    
SynonymsASP2    
Asp 2    
Aspartyl protease 2    
BACE    
BACE1    
Beta-site APP cleaving enzyme    
Beta-site APP cleaving enzyme 1    
Beta-site AbetaPP-cleaving enzyme    
Beta-site amyloid precursor protein cleaving enzyme    
Beta-site amyloid precursor protein cleaving enzyme 1    
Memapsin-2    
Membrane-associated aspartic protease 2    
Transmembrane aspartic protease    
DiseaseAlzheimer's disease
[ICD9: 331.0   ICD10: G30]
[1][2][3]
Drug(s)MK-8931Phase II/IIIAlzheimer's disease
CTS-21166Phase I completedAlzheimer's Disease[4]
AZD3293Phase IAlzheimer's disease
E2609Phase IAlzheimer's disease
HPP-854Phase IAlzheimer's disease
RG7129Phase IAlzheimer's disease
(-)-CATECHINGALLATEExperimentalNot Available[5]
(2S)-2'-methoxy kurarinoneExperimentalNot Available[6]
(S)-FLURBIPROFENExperimentalNot Available[7]
4-(2-aminoethyl)-2-cyclohexylphenolExperimentalNot Available[8]
4-(2-aminoethyl)-2-ethylphenolExperimentalNot Available[8]
4-(4-FLUOROBENZYL)PIPERIDINEExperimentalNot Available[8]
6-[2-(1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINEExperimentalNot Available[8]
7-PhloroetholExperimentalNot Available[9]
AP-2243ExperimentalNot Available[10]
Carbocyclic PeptidomimeticExperimentalNot Available[11]
DIECKOLExperimentalNot Available[9]
DIOXINODEHYDROECKOLExperimentalNot Available[9]
EckolExperimentalNot Available[9]
GRL-7234ExperimentalNot Available[12]
GSK-188909ExperimentalNot Available[13]
Glu-Leu-Asp-Leu-(CHOH-CH2)-Ala-Ala-Glu-PheExperimentalNot Available[14]
KMI-172ExperimentalNot Available[15]
KMI-494ExperimentalNot Available[15]
KMI-538ExperimentalNot Available[15]
KMI-596ExperimentalNot Available[16]
KURARINONEExperimentalNot Available[6]
KUSHENOL AExperimentalNot Available[6]
LEACHIANONE AExperimentalNot Available[6]
MMI-175ExperimentalNot Available[17]
N-(1-benzylpiperidin-4-yl)-4-sulfanylbutanamideExperimentalNot Available[8]
N~3~-(3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINEExperimentalNot Available[8]
N~3~-BENZYLPYRIDINE-2,3-DIAMINEExperimentalNot Available[8]
OM00-3ExperimentalNot Available[18]
Oxalyl-DAP derivativeExperimentalNot Available[19]
Oxalyl-DAP derivativeExperimentalNot Available[19]
PHLOROFUCOFUROECKOL AExperimentalNot Available[9]
R-flurbiprofenExperimentalNot Available[7]
TRIPHLOROETHOL AExperimentalNot Available[9]
bis(7)-tacrineExperimentalNot Available[20]
sophoraflavanone GExperimentalNot Available[6]
BioChemical ClassHydrolases acting on peptide bonds (Peptidases)    
EC NumberEC 3.4.23.46
PathwayAlzheimer's disease
UniProt IDP56817
PDB Structure1FKN; 1M4H; 1PY1; 1SGZ; 1TQF; 1UJJ; 1UJK; 1W50; 1W51; 1XN2; 1XN3; 1XS7; 1YM2; 1YM4; 2B8L; 2B8V; 2F3E; 2F3F; 2FDP; 2G94; 2HIZ; 2HM1; 2IQG; 2IRZ; 2IS0; 2NTR; 2OAH; 2OF0; 2OHK; 2OHL; 2OHM; 2OHN; 2OHP; 2OHQ; 2OHR; 2OHS; 2OHT; 2OHU; 2P4J; 2P83; 2P8H; 2PH6; 2PH8; 2Q11; 2Q15; 2QK5; 2QMD; 2QMF; 2QMG; 2QP8; 2QU2; 2QU3; 2QZK; 2QZL; 2VA5; 2VA6; 2VA7; 2VIE; 2VIJ; 2VIY; 2VIZ; 2VJ6; 2VJ7; 2VJ9; 2VKM; 2VNM; 2VNN; 2WEZ; 2WF0; 2WF1; 2WF2; 2WF3; 2WF4; 2WJO; 2XFI; 2XFJ; 2XFK; 2ZDZ; 2ZE1; 2ZHR; 2ZHS; 2ZHT; 2ZHU; 2ZHV; 2ZJH; 2ZJI; 2ZJJ; 2ZJK; 2ZJL; 2ZJM; 2ZJN; 3BRA; 3BUF; 3BUG; 3BUH; 3CIB; 3CIC; 3CID; 3CKP; 3CKR; 3DM6; 3DUY; 3DV1; 3DV5; 3EXO; 3FKT; 3H0B; 3HVG; 3HW1; 3I25; 3IGB; 3IN3; 3IN4; 3IND; 3INE; 3INF; 3INH; 3IVH; 3IVI; 3IXJ; 3IXK; 3K5C; 3K5D; 3K5F; 3K5G; 3KMX; 3KMY; 3KN0; 3KYR; 3L38; 3L3A; 3L58; 3L59; 3L5B; 3L5C; 3L5D; 3L5E; 3L5F; 3LHG; 3LNK; 3LPI; 3LPJ; 3LPK; 3MSJ; 3MSK; 3MSL; 3N4L; 3NSH; 3OHF; 3OHH; 3OOZ; 3PI5; 3QBH; 3QI1; 3R1G; 3R2F; 3RSV; 3RSX; 3RTH; 3RTM; 3RTN; 3RU1; 3RVI; 3S2O; 3S7L; 3S7M; 3SKF; 3SKG; 3TPJ; 3TPL; 3TPP; 3TPR; 3U6A; 3UDH; 3UDJ; 3UDK; 3UDM; 3UDN; 3UDP; 3UDQ; 3UDR; 3UDY; 3UFL; 3UQP; 3UQR; 3UQU; 3UQW; 3UQX; 3VEU; 3VF3; 3VG1; 3VV6; 3VV7; 3VV8; 3ZMG; 3ZOV; 4ACU; 4ACX; 4AZY; 4B00; 4B05; 4B1C; 4B1D; 4B1E; 4D83; 4D85; 4D88; 4D89; 4D8C; 4DH6; 4DI2; 4DJU; 4DJV; 4DJW; 4DJX; 4DJY; 4DPF; 4DPI; 4DUS; 4DV9; 4DVF; 4EWO; 4EXG; 4FCO; 4FGX; 4FM7; 4FM8; 4FRI; 4FRJ; 4FRK; 4FRS; 4FS4; 4FSE; 4FSL; 4GID; 4H1E; 4H3F; 4H3G; 4H3I; 4H3J; 4HA5; 4HZT; 4I0E; 4I0F; 4I0G; 4I0H; 4I0J; 4I0Z; 4I10; 4I11; 4I12; 4I1C; 4J0T; 4J0V; 4J0Y; 4J0Z; 4J17; 4J1C; 4J1E; 4J1F; 4J1H; 4J1I; 4J1K; 4JOO; 4JP9; 4JPC; 4JPE.    
FunctionResponsible for the proteolytic processing of the amyloid precursor protein (app). Cleaves at the amino 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 liquid.    
SequenceMAQALPWLLLWMGAGVLPAHGTQHGIRLPLRSGLGGAPLGLRLPRETDEEPEEPGRRGSF VEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPFLHRYYQRQLSST YRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRANIAAITESDKFFINGSNWEGIL GLAYAEIARPDDSLEPFFDSLVKQTHVPNLFSLQLCGAGFPLNQSEVLASVGGSMIIGGI DHSLYTGSLWYTPIRREWYYEVIIVRVEINGQDLKMDCKEYNYDKSIVDSGTTNLRLPKK VFEAAVKSIKAASSTEKFPDGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRIT ILPQQYLRPVEDVATSQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSAC HVHDEFRTAAVEGPFVTLDMEDCGYNIPQTDESTLMTIAYVMAAICALFMLPLCLMVCQW RCLRCLRQQHDDFADDISLLK
Related US Patent6,326,393
6,432,933
6,562,783
Target ValidationClick to Find Target Validation Information.    
Inhibitor (-)-CATECHINGALLATE[5]
(2S)-2'-methoxy kurarinone[6]
(S)-FLURBIPROFEN[7]
4- (2-aminoethyl)-2-ethylphenol[8]
4- (4-FLUOROBENZYL)PIPERIDINE[8]
5,5-Diphenyl-2-iminohydantoin[21]
6-[2- (1H-INDOL-6-YL)ETHYL]PYRIDIN-2-AMINE[8]
7-Phloroethol[9]
AP-2243[10]
CTS-21166[4]
Carbocyclic Peptidomimetic[11]
DIECKOL[9]
DIOXINODEHYDROECKOL[9]
Eckol[9]
GRL-7234[12]
GSK-188909[13]
Glu-Leu-Asp-Leu- (CHOH-CH2)-Ala-Ala-Glu-Phe[14]
KMI-172[15]
KMI-494[15]
KMI-538[15]
KMI-596[16]
KURARINONE[6]
KUSHENOL A[6]
LEACHIANONE A[6]
MMI-175[17]
N- (1-benzylpiperidin-4-yl)-4-sulfanylbutanamide[8]
N~3~- (3-PYRIDIN-3-YLBENZYL)PYRIDINE-2,3-DIAMINE[8]
N~3~-BENZYLPYRIDINE-2,3-DIAMINE[8]
OM00-3[18]
Oxalyl-DAP derivative[19]
Oxalyl-DAP derivative[19]
PHLOROFUCOFUROECKOL A[9]
R-flurbiprofen[7]
TRIPHLOROETHOL A[9]
bis (7)-tacrine[20]
sophoraflavanone G[6]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1A furin-like convertase mediates propeptide cleavage of BACE, the Alzheimer's beta -secretase. J Biol Chem. 2000 Dec 1;275(48):37712-7. To Reference
Ref 2Dehydroepiandrosterone reduces expression and activity of BACE in NT2 neurons exposed to oxidative stress. Neurobiol Dis. 2003 Nov;14(2):291-301. To Reference
Ref 3BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron. 2004 Jan 8;41(1):27-33. To Reference
Ref 4Safety Study of CTS21166 to Treat Alzheimer Disease. U. S. National Institutes of Health. 2008 To Reference
Ref 5Bioorg Med Chem Lett. 2003 Nov 17;13(22):3905-8.Green tea catechins as a BACE1 (beta-secretase) inhibitor. To Reference
Ref 6Bioorg Med Chem. 2008 Jul 15;16(14):6669-74. Epub 2008 Jun 5.BACE1 inhibitory effects of lavandulyl flavanones from Sophora flavescens. To Reference
Ref 7Bioorg Med Chem Lett. 2006 Apr 15;16(8):2219-23. Epub 2006 Feb 7.The geminal dimethyl analogue of Flurbiprofen as a novel Abeta42 inhibitor and potential Alzheimer's disease modifying agent. To Reference
Ref 8Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE: The Protein Data Bank. Nucleic Acids Res. 2000 Jan 1;28(1):235-42. To Reference
Ref 9Bioorg Med Chem Lett. 2010 Jun 1;20(11):3211-5. Epub 2010 Apr 24.Molecular docking studies of phlorotannins from Eisenia bicyclis with BACE1 inhibitory activity. To Reference
Ref 10Bioorg Med Chem Lett. 2008 Jan 1;18(1):423-6. Epub 2007 Oct 4.Multi-target-directed coumarin derivatives: hAChE and BACE1 inhibitors as potential anti-Alzheimer compounds. To Reference
Ref 11J Med Chem. 2005 Aug 11;48(16):5175-90.Structure-based design, synthesis, and memapsin 2 (BACE) inhibitory activity of carbocyclic and heterocyclic peptidomimetics. To Reference
Ref 12J Med Chem. 2007 May 17;50(10):2399-407. Epub 2007 Apr 14.Design, synthesis, and X-ray structure of potent memapsin 2 (beta-secretase) inhibitors with isophthalamide derivatives as the P2-P3-ligands. To Reference
Ref 13Bioorg Med Chem Lett. 2009 Jul 1;19(13):3664-8. Epub 2009 Apr 17.Second generation of BACE-1 inhibitors. Part 1: The need for improved pharmacokinetics. To Reference
Ref 14J Med Chem. 2004 Nov 4;47(23):5791-7.Efficient evaluation of binding free energy using continuum electrostatics solvation. To Reference
Ref 15Bioorg Med Chem Lett. 2007 Mar 15;17(6):1629-33. Epub 2007 Jan 8.Design and synthesis of BACE1 inhibitors containing a novel norstatine derivative (2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyric acid. To Reference
Ref 16Bioorg Med Chem. 2010 May 1;18(9):3175-86. Epub 2010 Mar 21.Design of pentapeptidic BACE1 inhibitors with carboxylic acid bioisosteres at P1' and P4 positions. To Reference
Ref 17Overington JP, Al-Lazikani B, Hopkins AL: How many drug targets are there? Nat Rev Drug Discov. 2006 Dec;5(12):993-6. To Reference
Ref 18Bioorg Med Chem. 2007 Jun 15;15(12):4136-43. Epub 2007 Mar 30.Synthesis and biological evaluation of phosphino dipeptide isostere inhibitor of human beta-secretase (BACE1). To Reference
Ref 19Bioorg Med Chem Lett. 2005 Jan 3;15(1):211-5.Design and synthesis of highly active Alzheimer's beta-secretase (BACE1) inhibitors, KMI-420 and KMI-429, with enhanced chemical stability. To Reference
Ref 20J Med Chem. 2009 Sep 10;52(17):5365-79.Pyrano[3,2-c]quinoline-6-chlorotacrine hybrids as a novel family of acetylcholinesterase- and beta-amyloid-directed anti-Alzheimer compounds. To Reference
Ref 21J Med Chem. 2010 Feb 11;53(3):951-65.Discovery of cyclic acylguanidines as highly potent and selective beta-site amyloid cleaving enzyme (BACE) inhibitors: Part I--inhibitor design and validation. To Reference



 

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