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 T59328 Target Info
Target Name Epidermal growth factor receptor (EGFR)
Synonyms Receptor tyrosine-protein kinase erbB-1; Proto-oncogene c-ErbB-1; HER1; ERBB1; ERBB
Target Type Successful Target
Gene Name EGFR
Biochemical Class Kinase
UniProt ID
EGFR_HUMAN
Ligand General Information  Top
Ligand Name (2R)-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[5-[2-[4-[[4-(hydroxymethyl)piperidin-1-yl]methyl]phenyl]ethynyl]-3-oxo-7-(trifluoromethyl)-1H-isoindol-2-yl]-N-(1,3-thiazol-2-yl)acetamide Ligand Info
Canonical SMILES C1CC2=C(N=CN2C1)C(C(=O)NC3=NC=CS3)N4CC5=C(C4=O)C=C(C=C5C(F)(F)F)C#CC6=CC=C(C=C6)CN7CCC(CC7)CO
InChI 1S/C35H33F3N6O3S/c36-35(37,38)28-17-25(8-5-22-3-6-23(7-4-22)18-42-13-9-24(20-45)10-14-42)16-26-27(28)19-44(33(26)47)31(32(46)41-34-39-11-15-48-34)30-29-2-1-12-43(29)21-40-30/h3-4,6-7,11,15-17,21,24,31,45H,1-2,9-10,12-14,18-20H2,(H,39,41,46)/t31-/m1/s1
InChIKey PPUARJAODGRSLP-WJOKGBTCSA-N
PubChem Compound ID 165412416
Drug Binding Sites of Target  Top
PDB ID: 8A27      EGFR kinase domain in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide
Method X-ray diffraction Resolution 1.07 Å Mutation No [1]
PDB Sequence
QALLRILKET
710
EFKKIKVLGS
720
GAFGTVYKGL
730
WIPEGEKVKI
740
PVAIKELREA
750

TSPKANKEIL
760
DEAYVMASVD
770
NPHVCRLLGI
780
CLTSTVQLIT
790
QLMPFGCLLD
800

YVREHKDNIG
810
SQYLLNWCVQ
820
IAKGMNYLED
830
RRLVHRDLAA
840
RNVLVKTPQH
850

VKITDFGLAV
876
PIKWMALESI
886
LHRIYTHQSD
896
VWSYGVTVWE
906
LMTFGSKPYD
916

GIPASEISSI
926
LEKGERLPQP
936
PICTIDVYMI
946
MVKCWMIDAD
956
SRPKFRELII
966

EFSKMARDPQ
976
RYLVIQGDE
Residue
Distance (Å)
VAL726
4.088
ALA743
3.450
ILE744
4.105
LYS745
2.858
LEU747
3.677
GLU749
3.738
THR751
3.827
ALA755
4.486
ILE759
2.847
LEU760
4.958
GLU762
3.108
ALA763
3.177
Residue
Distance (Å)
MET766
3.304
CYS775
3.053
ARG776
3.699
LEU777
3.611
LEU788
3.345
ILE789
4.400
THR790
3.522
THR854
3.600
ASP855
2.852
PHE856
3.493
GLY857
2.924
LEU858
3.230
PDB ID: 8A2A      EGFR kinase domain in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide (form 2)
Method X-ray diffraction Resolution 1.43 Å Mutation No [1]
PDB Sequence
NQALLRILKE
709
TEFKKIKVLG
719
SGAFGTVYKG
729
LWIPEGEKVK
739
IPVAIKELRE
749

ATSPKANKEI
759
LDEAYVMASV
769
DNPHVCRLLG
779
ICLTSTVQLI
789
TQLMPFGCLL
799

DYVREHKDNI
809
GSQYLLNWCV
819
QIAKGMNYLE
829
DRRLVHRDLA
839
ARNVLVKTPQ
849

HVKITDFGLA
859
KLLGAEEKVP
877
IKWMALESIL
887
HRIYTHQSDV
897
WSYGVTVWEL
907

MTFGSKPYDG
917
IPASEISSIL
927
EKGERLPQPP
937
ICTIDVYMIM
947
VKCWMIDADS
957

RPKFRELIIE
967
FSKMARDPQR
977
YLVIQGDERM
987
HLPSPTDSNF
997
YRALMDVVDA
1013

DEYLIP
Residue
Distance (Å)
VAL726
3.953
ALA743
3.396
ILE744
4.039
LYS745
2.890
LEU747
3.856
THR751
4.069
ALA755
4.290
GLU758
4.433
ILE759
2.980
GLU762
3.123
ALA763
3.353
MET766
3.193
CYS775
3.057
Residue
Distance (Å)
ARG776
3.696
LEU777
3.418
LEU788
3.293
ILE789
4.274
THR790
3.308
THR854
3.582
ASP855
2.731
PHE856
3.407
GLY857
2.938
LEU858
3.471
LEU861
3.310
LEU862
3.786
GLY863
4.270
PDB ID: 8A2B      EGFR kinase domain (L858R/V948R) in complex with 2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-1-yl)-2-[6-[2-[4-[[4-(hydroxymethyl)-1-piperidyl]methyl]phenyl]ethynyl]-1-oxo-4-(trifluoromethyl)isoindolin-2-yl]-N-thiazol-2-yl-acetamide
Method X-ray diffraction Resolution 1.69 Å Mutation Yes [1]
PDB Sequence
ALLRILKETE
711
FKKIKVLGSG
721
AFGTVYKGLW
731
IPEGEKVKIP
741
VAIKELREAT
751

SPKANKEILD
761
EAYVMASVDN
771
PHVCRLLGIC
781
LTSTVQLITQ
791
LMPFGCLLDY
801

VREHKDNIGS
811
QYLLNWCVQI
821
AKGMNYLEDR
831
RLVHRDLAAR
841
NVLVKTPQHV
851

KITDFGRVPI
878
KWMALESILH
888
RIYTHQSDVW
898
SYGVTVWELM
908
TFGSKPYDGI
918

PASEISSILE
928
KGERLPQPPI
938
CTIDVYMIMR
948
KCWMIDADSR
958
PKFRELIIEF
968

SKMARDPQRY
978
LVIQGDERMH
988
LP
Residue
Distance (Å)
PHE723
3.680
VAL726
4.137
ALA743
3.488
ILE744
3.925
LYS745
2.770
LEU747
3.783
ARG748
4.187
GLU749
4.366
ALA750
4.329
ALA755
3.867
ILE759
2.934
GLU762
3.202
Residue
Distance (Å)
ALA763
3.284
MET766
3.188
CYS775
3.027
ARG776
3.680
LEU777
3.692
LEU788
3.441
ILE789
4.558
THR790
3.497
THR854
3.708
ASP855
2.889
PHE856
3.401
ARG858
2.983
References  Top
REF 1 Discovery of Novel Allosteric EGFR L858R Inhibitors for the Treatment of Non-Small-Cell Lung Cancer as a Single Agent or in Combination with Osimertinib. J Med Chem. 2022 Oct 13;65(19):13052-13073.

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