Target Binding Site Detail
| 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 | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | N-{(1s,2r)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-5-[methyl(methylsulfonyl)amino]-N'-[(1r)-1-phenylethyl]benzene-1,3-dicarboxamide | Ligand Info | |||
| Canonical SMILES | CC(C1=CC=CC=C1)NC(=O)C2=CC(=CC(=C2)N(C)S(=O)(=O)C)C(=O)NC(CC3=CC=CC=C3)C(CNCC4=CC(=CC=C4)OC)O | ||||
| InChI | 1S/C36H42N4O6S/c1-25(28-15-9-6-10-16-28)38-35(42)29-20-30(22-31(21-29)40(2)47(4,44)45)36(43)39-33(19-26-12-7-5-8-13-26)34(41)24-37-23-27-14-11-17-32(18-27)46-3/h5-18,20-22,25,33-34,37,41H,19,23-24H2,1-4H3,(H,38,42)(H,39,43)/t25-,33+,34-/m1/s1 | ||||
| InChIKey | HIQWWDCRULXYDF-SWROZOJRSA-N | ||||
| PubChem Compound ID | 24882306 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 5MCO CRYSTAL STRUCTURE OF BACE-1 IN COMPLEX WITH ACTIVE SITE INHIBITOR GRL-8234 AND EXOSITE PEPTIDE | ||||||
| Method | X-ray diffraction | Resolution | 2.49 Å | Mutation | Yes | [1] |
| PDB Sequence |
GRRGSFVEMV
64 DNLRGKSGQG74 YYVEMTVGSP84 PQTLNILVDT94 GSSNFAVGAA104 PHPFLHRYYQ 114 RQLSSTYRDL124 RKGVYVPYTQ134 GKWEGELGTD144 LVSIPHGPNV154 TVRANIAAIT 164 ESDKFFINGS174 NWEGILGLAY184 AEIARPDDSL194 EPFFDSLVKQ204 THVPNLFSLQ 214 LCGAASVGGS234 MIIGGIDHSL244 YTGSLWYTPI254 RREWYYEVII264 VRVEINGQDL 274 KMDCKEYNYD284 KSIVDSGTTN294 LRLPKKVFEA304 AVASIKAASS314 TEKFPDGFWL 324 GEQLVCWQAG334 TTPWNIFPVI344 SLYLMGEVTN354 QSFRITILPQ364 QYLRPVEDVA 374 TSQDDCYKFA384 ISQSSTGTVM394 GAVIMEGFYV404 VFDRARKRIG414 FAVSACHVHD 424 EFRTAAVEGP434 FVTLDMEDCG444 YNI
|
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|
|
GLY72
3.397
GLN73
3.665
GLY74
3.255
TYR75
4.011
LEU91
3.756
ASP93
2.647
GLY95
3.153
SER96
3.517
VAL130
4.106
PRO131
3.579
TYR132
3.445
THR133
3.316
GLN134
3.035
PHE169
3.645
ILE171
3.782
TRP176
3.671
|
|||||
| PDB ID: 2VKM Crystal structure of GRL-8234 bound to BACE (Beta-secretase) | ||||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | No | [2] |
| PDB Sequence |
GSFVEMVDNL
6 RGKSGQGYYV16 EMTVGSPPQT26 LNILVDTGSS36 NFAVGAAPHP46 FLHRYYQRQL 56 SSTYRDLRKG66 VYVPYTQGKW76 EGELGTDLVS86 IPHGPNVTVR96 ANIAAITESD 106 KFFINGSNWE116 GILGLAYAEI126 ARPDDSLEPF136 FDSLVKQTHV146 PNLFSLQLCG 156 AGFPLNQSEV166 LASVGGSMII176 GGIDHSLYTG186 SLWYTPIRRE196 WYYEVIIVRV 206 EINGQDLKMD216 CKEYNYDKSI226 VDSGTTNLRL236 PKKVFEAAVK246 SIKAASSTEK 256 FPDGFWLGEQ266 LVCWQAGTTP276 WNIFPVISLY286 LMGEVTNQSF296 RITILPQQYL 306 RPVEDVATSQ316 DDCYKFAISQ326 SSTGTVMGAV336 IMEGFYVVFD346 RARKRIGFAV 356 SACHVHDEFR366 TAAVEGPFVT376 LDMEDCGYN
|
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|
|
GLY11
4.238
GLN12
3.467
GLY13
3.238
TYR14
3.926
LEU30
3.384
ASP32
2.688
GLY34
3.101
SER35
3.113
SER36
4.527
VAL69
4.855
PRO70
3.539
TYR71
3.350
THR72
3.249
GLN73
3.008
GLY74
4.849
LYS107
4.830
PHE108
3.527
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Potent and Selective BACE-1 Peptide Inhibitors Lower Brain Abeta Levels Mediated by Brain Shuttle Transport. EBioMedicine. 2017 Oct;24:76-92. | ||||
| REF 2 | Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation. Bioorg Med Chem Lett. 2008 Feb 1;18(3):1031-6. | ||||
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