Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T79031 Target Info
Target Name Beta-secretase 1 (BACE1)
Synonyms Membrane-associated aspartic protease 2; Memapsin-2; KIAA1149; Beta-site amyloid precursor protein cleaving enzyme 1; Beta-site APP cleaving enzyme 1; BACE; Aspartyl protease 2; Asp 2; ASP2
Target Type Clinical trial Target
Gene Name BACE1
Biochemical Class Peptidase
UniProt ID
BACE1_HUMAN
Ligand General Information  Top
Ligand Name (6s)-2-Amino-6-(3'-Methoxybiphenyl-3-Yl)-3,6-Dimethyl-5,6-Dihydropyrimidin-4(3h)-One Ligand Info
Canonical SMILES CC1(CC(=O)N(C(=N1)N)C)C2=CC=CC(=C2)C3=CC(=CC=C3)OC
InChI 1S/C19H21N3O2/c1-19(12-17(23)22(2)18(20)21-19)15-8-4-6-13(10-15)14-7-5-9-16(11-14)24-3/h4-11H,12H2,1-3H3,(H2,20,21)/t19-/m0/s1
InChIKey LQOCXPOKEPYGTJ-IBGZPJMESA-N
PubChem Compound ID 17749735
Drug Binding Sites of Target  Top
PDB ID: 2VA6      X-ray crystal structure of beta secretase complexed with compound 24
Method X-ray diffraction Resolution 2.50 Å Mutation Yes [1]
PDB Sequence
FVEMVDNLRG
8
KSGQGYYVEM
18
TVGSPPQTLN
28
ILVDTGSSNF
38
AVGAAPHPFL
48

HRYYQRQLSS
58
TYRDLRKGVY
68
VPYTQGKWEG
78
ELGTDLVSIP
88
HGPNVTVRAN
98

IAAITESDKF
108
FINGSNWEGI
118
LGLAYAEIAR
128
PDDSLEPFFD
138
SLVKQTHVPN
148

LFSLQLCGAS
169
VGGSMIIGGI
179
DHSLYTGSLW
189
YTPIRREWYY
199
EVIIVRVEIN
209

GQDLKMDCKE
219
YNYDKSIVDS
229
GTTNLRLPKK
239
VFEAAVKSIK
249
AASSTEKFPD
259

GFWLGEQLVC
269
WQAGTTPWNI
279
FPVISLYLMG
289
EVTNQSFRIT
299
ILPQQYLRPV
309

EDVATSQDDC
319
YKFAISQSST
329
GTVMGAVIME
339
GFYVVFDRAR
349
KRIGFAVSAC
359

HVHDEFRTAA
369
VEGPFVTLDM
379
EDCGYNI
Residue
Distance (Å)
LYS9
4.202
SER10
2.930
GLY11
3.518
GLN12
3.563
GLY13
3.158
TYR14
4.750
LEU30
3.832
ASP32
2.760
GLY34
3.659
SER35
3.952
TYR71
3.497
Residue
Distance (Å)
PHE108
3.677
ILE110
4.150
TRP115
4.046
ILE118
3.384
ASP228
2.645
SER229
3.497
GLY230
2.935
THR231
3.189
THR232
3.854
ALA335
4.491
PDB ID: 4FS4      Structure of BACE Bound to (S)-4-(3'-methoxy-[1,1'-biphenyl]-3-yl)-1,4-dimethyl-6-oxotetrahydropyrimidin-2(1H)-iminium
Method X-ray diffraction Resolution 1.74 Å Mutation No [2]
PDB Sequence
GSFVEMVDNL
67
RGKSGQGYYV
77
EMTVGSPPQT
87
LNILVDTGSS
97
NFAVGAAPHP
107

FLHRYYQRQL
117
SSTYRDLRKG
127
VYVPYTQGKW
137
EGELGTDLVS
147
IPHGPNVTVR
157

ANIAAITESD
167
KFFINGSNWE
177
GILGLAYAEI
187
ARPDDSLEPF
197
FDSLVKQTHV
207

PNLFSLQLCG
217
AGFPLNQSEV
227
LASVGGSMII
237
GGIDHSLYTG
247
SLWYTPIRRE
257

WYYEVIIVRV
267
EINGQDLKMD
277
CKEYNYDKSI
287
VDSGTTNLRL
297
PKKVFEAAVK
307

SIKAASSTEK
317
FPDGFWLGEQ
327
LVCWQAGTTP
337
WNIFPVISLY
347
LMGEVTNQSF
357

RITILPQQYL
367
RPVEDVATSQ
377
DDCYKFAISQ
387
SSTGTVMGAV
397
IMEGFYVVFD
407

RARKRIGFAV
417
SACHVHDEFR
427
TAAVEGPFVT
437
LDMEDCGYNI
447
Residue
Distance (Å)
LYS70
4.530
SER71
3.230
GLY72
3.487
GLN73
3.528
GLY74
3.447
TYR75
4.828
LEU91
3.898
ASP93
2.611
GLY95
3.922
SER96
4.276
TYR132
3.415
Residue
Distance (Å)
PHE169
3.645
ILE171
3.450
TRP176
3.732
ILE179
3.677
ASP289
2.914
SER290
3.323
GLY291
3.107
THR292
3.171
THR293
3.496
ALA396
3.956
References  Top
REF 1 Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency. J Med Chem. 2007 Nov 29;50(24):5912-25.
REF 2 A Potent and Orally Efficacious, Hydroxyethylamine-Based Inhibitor of beta-Secretase. ACS Med Chem Lett. 2012 Mar 29;3(11):886-91.

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