Fluorine in PDB 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)

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 (Form 2)

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 (Form 2):
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 (Form 2), PDB code: 8a2a 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) 57.31 / 1.43
Space group P 21 21 21
Cell size a, b, c (Å), α, β, γ (°) 47.184, 68.591, 104.286, 90, 90, 90
R / Rfree (%) 18.8 / 22.3

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 (Form 2) (pdb code 8a2a). 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 (Form 2), PDB code: 8a2a:
Jump to Fluorine binding site number: 1; 2; 3;

Fluorine binding site 1 out of 3 in 8a2a

Go back to Fluorine Binding Sites List in 8a2a
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 (Form 2)


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 (Form 2) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:26.3
occ:1.00
 F13 A:KY91101 0.0 26.3 1.0
C12 A:KY91101 1.4 21.6 1.0
F14 A:KY91101 2.2 25.5 1.0
F15 A:KY91101 2.3 25.4 1.0
C11 A:KY91101 2.3 20.2 1.0
C10 A:KY91101 2.6 19.7 1.0
O A:ILE759 3.0 27.5 1.0
N A:ALA763 3.4 22.5 1.0
C16 A:KY91101 3.5 18.6 1.0
CG2 A:ILE759 3.6 25.9 1.0
CB A:GLU762 3.6 33.0 1.0
CA A:ALA763 3.7 21.3 1.0
CB A:ALA763 3.7 21.8 1.0
C A:ILE759 3.8 27.4 1.0
CD1 A:LEU861 3.9 37.6 1.0
C A:GLU762 3.9 23.3 1.0
CA A:ILE759 3.9 26.6 1.0
C9 A:KY91101 4.0 22.1 1.0
CG A:GLU762 4.0 38.9 1.0
CB A:ILE759 4.3 26.6 1.0
CA A:GLU762 4.4 28.3 1.0
C37 A:KY91101 4.4 17.2 1.0
O A:GLU762 4.5 24.6 1.0
C17 A:KY91101 4.7 18.3 1.0
CD2 A:LEU788 4.8 20.7 1.0
O A:GLY857 4.8 25.4 1.0
C8 A:KY91101 4.9 24.9 1.0
C39 A:KY91101 4.9 20.1 1.0
CG1 A:ILE759 4.9 26.8 1.0
N A:GLU762 4.9 31.5 1.0

Fluorine binding site 2 out of 3 in 8a2a

Go back to Fluorine Binding Sites List in 8a2a
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 (Form 2)


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 (Form 2) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:25.5
occ:1.00
 F14 A:KY91101 0.0 25.5 1.0
C12 A:KY91101 1.4 21.6 1.0
F15 A:KY91101 2.1 25.4 1.0
F13 A:KY91101 2.2 26.3 1.0
C11 A:KY91101 2.3 20.2 1.0
C16 A:KY91101 3.0 18.6 1.0
CG A:GLU762 3.1 38.9 1.0
CG A:MET766 3.2 21.7 1.0
C10 A:KY91101 3.3 19.7 1.0
C37 A:KY91101 3.3 17.2 1.0
O A:GLY857 3.4 25.4 1.0
CB A:GLU762 3.6 33.0 1.0
C A:GLU762 3.8 23.3 1.0
N A:ALA763 3.9 22.5 1.0
O A:GLU762 3.9 24.6 1.0
CA A:ALA763 4.0 21.3 1.0
CA A:GLY857 4.1 19.5 1.0
C A:GLY857 4.2 22.9 1.0
C17 A:KY91101 4.3 18.3 1.0
SD A:MET766 4.3 24.9 1.0
CD1 A:LEU861 4.3 37.6 1.0
CB A:MET766 4.3 21.8 1.0
CA A:GLU762 4.4 28.3 1.0
CE A:MET766 4.5 28.3 1.0
C9 A:KY91101 4.5 22.1 1.0
CD A:GLU762 4.5 44.6 1.0
N19 A:KY91101 4.7 17.2 1.0
CB A:ALA763 4.7 21.8 1.0
O A:ILE759 4.8 27.5 1.0
C39 A:KY91101 4.9 20.1 1.0
OE1 A:GLU762 5.0 58.6 1.0

Fluorine binding site 3 out of 3 in 8a2a

Go back to Fluorine Binding Sites List in 8a2a
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 (Form 2)


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 (Form 2) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1101

b:25.4
occ:1.00
 F15 A:KY91101 0.0 25.4 1.0
C12 A:KY91101 1.4 21.6 1.0
F14 A:KY91101 2.1 25.5 1.0
F13 A:KY91101 2.3 26.3 1.0
C11 A:KY91101 2.5 20.2 1.0
C16 A:KY91101 2.9 18.6 1.0
C37 A:KY91101 3.0 17.2 1.0
CD2 A:LEU777 3.4 21.6 1.0
CA A:ALA763 3.4 21.3 1.0
C10 A:KY91101 3.6 19.7 1.0
CB A:ALA763 3.6 21.8 1.0
CG A:MET766 3.7 21.7 1.0
CD2 A:LEU788 3.8 20.7 1.0
N A:ALA763 3.9 22.5 1.0
CB A:MET766 4.2 21.8 1.0
C17 A:KY91101 4.3 18.3 1.0
N19 A:KY91101 4.4 17.2 1.0
C A:GLU762 4.4 23.3 1.0
O A:GLU762 4.6 24.6 1.0
C A:ALA763 4.7 21.2 1.0
CG A:LEU777 4.7 21.2 1.0
O A:ILE759 4.7 27.5 1.0
C9 A:KY91101 4.8 22.1 1.0
O A:ALA763 4.8 22.1 1.0
CD1 A:LEU777 4.9 20.6 1.0
CD1 A:LEU788 4.9 21.4 1.0
CG A:LEU788 5.0 20.4 1.0
CG A:GLU762 5.0 38.9 1.0
C18 A:KY91101 5.0 17.4 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 16:23:44 2024

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