Fluorine in PDB 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

Enzymatic activity of 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

All present enzymatic activity of 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:
2.7.10.1;

Protein crystallography data

The structure of 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, PDB code: 8a2b was solved by A.Kuglstatter, A.Ehler, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 65.29 / 1.69
Space group P 61 2 2
Cell size a, b, c (Å), α, β, γ (°) 75.387, 75.387, 214.953, 90, 90, 120
R / Rfree (%) 21 / 25.8

Fluorine Binding Sites:

The binding sites of Fluorine atom in the 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 (pdb code 8a2b). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 3 binding sites of Fluorine where determined in the 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, PDB code: 8a2b:
Jump to Fluorine binding site number: 1; 2; 3;

Fluorine binding site 1 out of 3 in 8a2b

Go back to Fluorine Binding Sites List in 8a2b
Fluorine binding site 1 out of 3 in the 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


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of 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 within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:27.5
occ:1.00
 F13 A:KY91101 0.0 27.5 1.0
C12 A:KY91101 1.3 25.2 1.0
F14 A:KY91101 2.1 30.6 1.0
F15 A:KY91101 2.2 27.6 1.0
C11 A:KY91101 2.4 21.9 1.0
C16 A:KY91101 2.9 18.9 1.0
C37 A:KY91101 3.1 17.5 1.0
C10 A:KY91101 3.5 21.5 1.0
CA A:ALA763 3.6 21.4 1.0
CB A:ALA763 3.7 21.8 1.0
CD2 A:LEU777 3.7 25.8 1.0
CD2 A:LEU788 3.8 19.0 1.0
CD1 A:LEU788 4.0 20.7 1.0
N A:ALA763 4.0 22.7 1.0
CG A:MET766 4.1 22.9 1.0
C17 A:KY91101 4.2 19.0 1.0
N19 A:KY91101 4.5 18.1 1.0
CG A:LEU788 4.5 18.8 1.0
CB A:MET766 4.5 21.7 1.0
O A:ILE759 4.6 20.4 1.0
C A:GLU762 4.6 23.2 1.0
C9 A:KY91101 4.7 21.9 1.0
O A:GLU762 4.8 22.9 1.0
CG2 A:ILE759 5.0 20.8 1.0
C A:ALA763 5.0 25.1 1.0
CD1 A:LEU777 5.0 21.2 1.0
CG A:LEU777 5.0 21.6 1.0

Fluorine binding site 2 out of 3 in 8a2b

Go back to Fluorine Binding Sites List in 8a2b
Fluorine binding site 2 out of 3 in the 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


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of 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 within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:30.6
occ:1.00
 F14 A:KY91101 0.0 30.6 1.0
C12 A:KY91101 1.4 25.2 1.0
F13 A:KY91101 2.1 27.5 1.0
F15 A:KY91101 2.2 27.6 1.0
C11 A:KY91101 2.4 21.9 1.0
C10 A:KY91101 2.8 21.5 1.0
O A:ILE759 2.9 20.4 1.0
N A:ALA763 3.3 22.7 1.0
CB A:GLU762 3.6 25.4 1.0
C16 A:KY91101 3.7 18.9 1.0
CA A:ALA763 3.7 21.4 1.0
CG2 A:ILE759 3.7 20.8 1.0
C A:GLU762 3.8 23.2 1.0
CB A:ALA763 3.8 21.8 1.0
C A:ILE759 3.8 21.2 1.0
CA A:ILE759 3.9 21.6 1.0
CG A:GLU762 4.0 30.9 1.0
CA A:GLU762 4.1 24.0 1.0
C9 A:KY91101 4.2 21.9 1.0
CB A:ILE759 4.3 20.9 1.0
C37 A:KY91101 4.5 17.5 1.0
O A:GLU762 4.5 22.9 1.0
N A:GLU762 4.7 22.6 1.0
C17 A:KY91101 4.8 19.0 1.0
CD2 A:LEU788 4.9 19.0 1.0
CG1 A:ILE759 4.9 20.4 1.0
CG A:MET766 5.0 22.9 1.0

Fluorine binding site 3 out of 3 in 8a2b

Go back to Fluorine Binding Sites List in 8a2b
Fluorine binding site 3 out of 3 in the 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


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of 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 within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:27.6
occ:1.00
 F15 A:KY91101 0.0 27.6 1.0
C12 A:KY91101 1.4 25.2 1.0
F13 A:KY91101 2.2 27.5 1.0
F14 A:KY91101 2.2 30.6 1.0
C11 A:KY91101 2.4 21.9 1.0
C16 A:KY91101 3.0 18.9 1.0
CG A:MET766 3.2 22.9 1.0
CG A:GLU762 3.2 30.9 1.0
C37 A:KY91101 3.3 17.5 1.0
C10 A:KY91101 3.4 21.5 1.0
NH1 A:ARG858 3.7 22.5 0.5
CB A:GLU762 3.7 25.4 1.0
C A:GLU762 3.8 23.2 1.0
N A:ALA763 3.9 22.7 1.0
O A:GLU762 4.0 22.9 1.0
CA A:ALA763 4.2 21.4 1.0
C17 A:KY91101 4.3 19.0 1.0
CB A:MET766 4.3 21.7 1.0
CA A:GLU762 4.3 24.0 1.0
SD A:MET766 4.3 30.7 1.0
CZ A:ARG858 4.4 27.6 0.5
CD A:GLU762 4.5 34.8 1.0
C9 A:KY91101 4.6 21.9 1.0
CG A:ARG858 4.6 31.1 0.5
N19 A:KY91101 4.6 18.1 1.0
OE2 A:GLU762 4.8 40.4 1.0
CB A:ALA763 4.8 21.8 1.0
CD A:ARG858 4.8 31.1 0.5
O A:ILE759 4.8 20.4 1.0
NE A:ARG858 4.9 26.9 0.5
CE A:MET766 4.9 26.3 1.0
C39 A:KY91101 5.0 20.4 1.0

Reference:

U.Obst-Sander, A.Ricci, B.Kuhn, T.Friess, P.Koldewey, A.Kuglstatter, D.Hewings, A.Goergler, S.Steiner, D.Rueher, M.P.Imhoff, N.Raschetti, H.P.Marty, A.Dietzig, C.Rynn, A.Ehler, D.Burger, M.Kornacker, J.P.Schaffland, F.Herting, W.Pao, J.R.Bischoff, B.Martoglio, Y.Alice Nagel, G.Jaeschke. 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. V. 65 13052 2022.
ISSN: ISSN 0022-2623
PubMed: 36178776
DOI: 10.1021/ACS.JMEDCHEM.2C00893
Page generated: Fri Aug 2 16:23:47 2024

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