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 N-[(1s,2r)-1-(3,5-Difluorobenzyl)-2-Hydroxy-3-({1-[3-(1h-Pyrazol-1-Yl)phenyl]cyclohexyl}amino)propyl]acetamide Ligand Info
Canonical SMILES CC(=O)NC(CC1=CC(=CC(=C1)F)F)C(CNC2(CCCCC2)C3=CC(=CC=C3)N4C=CC=N4)O
InChI 1S/C27H32F2N4O2/c1-19(34)32-25(15-20-13-22(28)17-23(29)14-20)26(35)18-30-27(9-3-2-4-10-27)21-7-5-8-24(16-21)33-12-6-11-31-33/h5-8,11-14,16-17,25-26,30,35H,2-4,9-10,15,18H2,1H3,(H,32,34)/t25-,26+/m0/s1
InChIKey QXNFPOMRKODYSK-IZZNHLLZSA-N
PubChem Compound ID 45486979
Drug Binding Sites of Target  Top
PDB ID: 4I0J      SPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
Method X-ray diffraction Resolution 1.99 Å Mutation No [1]
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
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

RPVSQDDCYK
382
FAISQSSTGT
392
VMGAVIMEGF
402
YVVFDRARKR
412
IGFAVSACHV
422

HDEFRTAAVE
432
GPFVTLDMED
442
CGYNIPQTDE
452
SRSHHHHH
Residue
Distance (Å)
GLN73
4.831
LEU91
3.621
ASP93
2.413
GLY95
3.325
SER96
3.726
SER97
4.689
VAL130
3.802
PRO131
3.325
TYR132
3.245
THR133
2.904
GLN134
4.330
GLY135
3.571
LYS136
4.641
LYS168
4.187
PHE169
3.211
Residue
Distance (Å)
ILE171
3.399
TRP176
3.322
ILE179
3.785
ILE187
3.656
ARG189
3.974
TYR259
2.872
LYS285
3.865
ILE287
3.711
ASP289
2.803
GLY291
3.150
THR292
3.853
ARG296
3.932
THR390
3.651
VAL393
3.926
PDB ID: 3N4L      BACE-1 in complex with ELN380842
Method X-ray diffraction Resolution 2.70 Å Mutation No [2]
PDB Sequence
SFVEMVDNLR
13
GKSGQGYYVE
23
MTVGSPPQTL
33
NILVDTGSSN
43
FAVGAAPHPF
53

LHRYYQRQLS
63
STYRDLRKGV
73
YVPYTQGKWE
83
GELGTDLVSI
93
PHGPNVTVRA
103

NIAAITESDK
113
FFINGSNWEG
123
ILGLAYAEIA
133
RPDDSLEPFF
143
DSLVKQTHVP
153

NLFSLQLCGS
175
VGGSMIIGGI
185
DHSLYTGSLW
195
YTPIRREWYY
205
EVIIVRVEIN
215

GQDLKMDCKE
225
YNYDKSIVDS
235
GTTNLRLPKK
245
VFEAAVKSIK
255
AASSTEKFPD
265

GFWLGEQLVC
275
WQAGTTPWNI
285
FPVISLYLMG
295
EVTNQSFRIT
305
ILPQQYLRPV
315

EDVSQDDCYK
327
FAISQSSTGT
337
VMGAVIMEGF
347
YVVFDRARKR
357
IGFAVSACHV
367

HDEFRTAAVE
377
GPFVTLDMED
387
CGYNI
Residue
Distance (Å)
GLN18
4.442
LEU36
3.727
ASP38
2.651
GLY40
2.941
SER41
3.739
SER42
4.688
VAL75
4.097
PRO76
3.199
TYR77
3.397
THR78
2.982
GLN79
4.271
GLY80
4.026
LYS113
4.286
PHE114
3.092
Residue
Distance (Å)
ILE116
3.998
TRP121
3.717
ILE124
3.973
ILE132
3.617
ARG134
4.573
TYR204
2.593
LYS230
3.973
ILE232
3.551
ASP234
2.997
GLY236
2.972
THR237
3.992
ARG241
4.335
THR335
3.794
VAL338
3.981
References  Top
REF 1 SPR and structural analysis yield insight towards mechanism of inhibition of BACE inhibitors
REF 2 Improving the permeability of the hydroxyethylamine BACE-1 inhibitors: structure-activity relationship of P2' substituents. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4789-94.

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