Fluorine in PDB 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

Enzymatic activity of 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

All present enzymatic activity of 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:
2.7.10.1;

Protein crystallography data

The structure of 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, PDB code: 8a27 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) 65.61 / 1.07
Space group C 1 2 1
Cell size a, b, c (Å), α, β, γ (°) 119.28, 34.915, 84.334, 90, 128.92, 90
R / Rfree (%) 12.4 / 16

Fluorine Binding Sites:

The binding sites of Fluorine atom in the 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 (pdb code 8a27). 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 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: 8a27:
Jump to Fluorine binding site number: 1; 2; 3;

Fluorine binding site 1 out of 3 in 8a27

Go back to Fluorine Binding Sites List in 8a27
Fluorine binding site 1 out of 3 in the 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


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 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:F1102

b:16.6
occ:1.00
 F13 A:KY91102 0.0 16.6 1.0
C12 A:KY91102 1.3 14.1 1.0
F14 A:KY91102 2.1 17.3 1.0
F15 A:KY91102 2.1 18.8 1.0
C11 A:KY91102 2.4 11.2 1.0
C10 A:KY91102 2.7 12.5 1.0
O A:ILE759 2.8 11.8 1.0
N A:ALA763 3.2 10.4 1.0
CB A:GLU762 3.4 13.2 1.0
C16 A:KY91102 3.6 10.6 1.0
CA A:ALA763 3.6 9.9 1.0
C A:GLU762 3.7 11.2 1.0
CG2 A:ILE759 3.7 12.3 1.0
C A:ILE759 3.7 10.5 1.0
CB A:ALA763 3.8 10.8 1.0
CG A:GLU762 3.8 21.6 1.0
CA A:ILE759 3.9 10.6 1.0
CA A:GLU762 4.0 12.1 1.0
C9 A:KY91102 4.1 12.3 1.0
O A:GLU762 4.4 11.4 1.0
CB A:ILE759 4.4 11.8 1.0
C37 A:KY91102 4.4 10.4 1.0
N A:GLU762 4.5 11.2 1.0
C17 A:KY91102 4.8 10.6 1.0
O A:GLY857 4.8 90.8 1.0
N A:LEU760 5.0 10.5 1.0
CG1 A:ILE759 5.0 13.2 1.0
CD2 A:LEU788 5.0 14.2 1.0
C39 A:KY91102 5.0 11.0 1.0

Fluorine binding site 2 out of 3 in 8a27

Go back to Fluorine Binding Sites List in 8a27
Fluorine binding site 2 out of 3 in the 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


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 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:F1102

b:17.3
occ:1.00
 F14 A:KY91102 0.0 17.3 1.0
C12 A:KY91102 1.4 14.1 1.0
F15 A:KY91102 2.1 18.8 1.0
F13 A:KY91102 2.1 16.6 1.0
C11 A:KY91102 2.4 11.2 1.0
C16 A:KY91102 2.9 10.6 1.0
CG A:GLU762 3.1 21.6 1.0
C37 A:KY91102 3.2 10.4 1.0
CG A:MET766 3.3 12.5 1.0
C10 A:KY91102 3.4 12.5 1.0
CB A:GLU762 3.5 13.2 1.0
O A:GLY857 3.5 90.8 1.0
C A:GLU762 3.7 11.2 1.0
N A:ALA763 3.7 10.4 1.0
O A:GLU762 3.8 11.4 1.0
CA A:ALA763 4.0 9.9 1.0
CA A:GLU762 4.2 12.1 1.0
CA A:GLY857 4.2 122.5 1.0
C17 A:KY91102 4.3 10.6 1.0
CB A:MET766 4.3 11.8 1.0
C A:GLY857 4.3 83.3 1.0
SD A:MET766 4.4 16.0 1.0
CD A:GLU762 4.4 28.9 1.0
N19 A:KY91102 4.5 10.1 1.0
C9 A:KY91102 4.6 12.3 1.0
O A:ILE759 4.6 11.8 1.0
OE1 A:GLU762 4.7 40.0 1.0
CB A:ALA763 4.7 10.8 1.0

Fluorine binding site 3 out of 3 in 8a27

Go back to Fluorine Binding Sites List in 8a27
Fluorine binding site 3 out of 3 in the 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


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 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:F1102

b:18.8
occ:1.00
 F15 A:KY91102 0.0 18.8 1.0
C12 A:KY91102 1.3 14.1 1.0
F14 A:KY91102 2.1 17.3 1.0
F13 A:KY91102 2.1 16.6 1.0
C11 A:KY91102 2.3 11.2 1.0
C16 A:KY91102 2.9 10.6 1.0
C37 A:KY91102 3.1 10.4 1.0
C10 A:KY91102 3.4 12.5 1.0
CA A:ALA763 3.6 9.9 1.0
CD2 A:LEU788 3.7 14.2 1.0
CD2 A:LEU777 3.7 11.6 1.0
CB A:ALA763 3.7 10.8 1.0
N A:ALA763 3.9 10.4 1.0
CG A:MET766 4.2 12.5 1.0
C17 A:KY91102 4.3 10.6 1.0
CD1 A:LEU788 4.3 12.9 1.0
C A:GLU762 4.5 11.2 1.0
O A:ILE759 4.5 11.8 1.0
N19 A:KY91102 4.5 10.1 1.0
CG A:LEU788 4.6 11.0 1.0
C9 A:KY91102 4.6 12.3 1.0
CB A:MET766 4.6 11.8 1.0
O A:GLU762 4.7 11.4 1.0
CG2 A:ILE759 4.8 12.3 1.0
CG A:LEU777 4.8 9.4 1.0
C A:ALA763 4.9 9.8 1.0
CD1 A:LEU777 4.9 10.3 1.0
C39 A:KY91102 5.0 11.0 1.0
CB A:GLU762 5.0 13.2 1.0
CG A:GLU762 5.0 21.6 1.0
C18 A:KY91102 5.0 11.1 1.0
O36 A:KY91102 5.0 10.4 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 16:23:45 2024

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