Fluorine in PDB 8a2d: Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide

Enzymatic activity of Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide

All present enzymatic activity of Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-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-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide, PDB code: 8a2d 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) 65.40 / 1.11
Space group C 1 2 1
Cell size a, b, c (Å), α, β, γ (°) 119.619, 34.951, 83.934, 90, 128.81, 90
R / Rfree (%) 16.3 / 17.9

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide (pdb code 8a2d). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 2 binding sites of Fluorine where determined in the Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide, PDB code: 8a2d:
Jump to Fluorine binding site number: 1; 2;

Fluorine binding site 1 out of 2 in 8a2d

Go back to Fluorine Binding Sites List in 8a2d
Fluorine binding site 1 out of 2 in the Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-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-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1103

b:14.5
occ:1.00
 F22 A:KXY1103 0.0 14.5 1.0
C21 A:KXY1103 1.4 11.5 1.0
F23 A:KXY1103 2.1 13.2 1.0
C20 A:KXY1103 2.3 9.8 1.0
C15 A:KXY1103 2.9 8.9 1.0
C14 A:KXY1103 3.1 8.7 1.0
CG A:GLU762 3.2 12.2 0.5
CG A:MET766 3.4 10.6 1.0
CB A:GLU762 3.4 13.6 0.5
N A:ALA763 3.4 8.8 1.0
C A:GLU762 3.4 9.6 1.0
CB A:GLU762 3.5 11.5 0.5
CD A:GLU762 3.5 15.2 0.5
C19 A:KXY1103 3.5 10.6 1.0
NH1 A:ARG858 3.5 27.4 1.0
O A:GLU762 3.6 9.6 1.0
CA A:ALA763 3.7 8.7 1.0
OE2 A:GLU762 3.8 18.1 0.5
CA A:GLU762 4.0 10.9 0.5
CA A:GLU762 4.0 10.1 0.5
OE1 A:GLU762 4.1 20.5 0.5
CZ A:ARG858 4.2 25.9 1.0
O A:ILE759 4.3 10.1 1.0
C16 A:KXY1103 4.3 9.4 1.0
OE2 A:GLU762 4.4 25.5 0.5
CB A:MET766 4.4 9.8 1.0
N13 A:KXY1103 4.4 9.1 1.0
CB A:ALA763 4.4 8.7 1.0
CG A:GLU762 4.5 16.7 0.5
NE A:ARG858 4.5 26.8 1.0
SD A:MET766 4.6 12.9 1.0
C18 A:KXY1103 4.7 11.3 1.0
CD A:GLU762 4.7 20.2 0.5
CD2 A:LEU777 4.9 9.2 1.0
C A:ALA763 4.9 9.3 1.0

Fluorine binding site 2 out of 2 in 8a2d

Go back to Fluorine Binding Sites List in 8a2d
Fluorine binding site 2 out of 2 in the Egfr Kinase Domain (L858R/V948R) in Complex with 2-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-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-[4- (Difluoromethyl)-6-[2-[4-[[4-(Hydroxymethyl)-1- Piperidyl]Methyl]Phenyl]Ethynyl]-7-Methyl-Indazol-2-Yl]-2-Spiro[6,7- Dihydropyrrolo[1,2-C]Imidazole-5,1'-Cyclopropane]-1-Yl-N-Thiazol-2- Yl-Acetamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F1103

b:13.2
occ:1.00
 F23 A:KXY1103 0.0 13.2 1.0
C21 A:KXY1103 1.4 11.5 1.0
F22 A:KXY1103 2.1 14.5 1.0
C20 A:KXY1103 2.3 9.8 1.0
C15 A:KXY1103 3.0 8.9 1.0
C19 A:KXY1103 3.4 10.6 1.0
C14 A:KXY1103 3.4 8.7 1.0
CB A:ALA763 3.4 8.7 1.0
CD2 A:LEU788 3.5 12.3 1.0
CA A:ALA763 3.5 8.7 1.0
N A:ALA763 3.7 8.8 1.0
CD2 A:LEU777 3.9 9.2 1.0
O A:ILE759 3.9 10.1 1.0
CD1 A:LEU788 4.0 11.3 1.0
CG2 A:ILE759 4.2 10.6 1.0
C16 A:KXY1103 4.3 9.4 1.0
CG A:LEU788 4.3 10.0 1.0
C A:GLU762 4.4 9.6 1.0
C18 A:KXY1103 4.5 11.3 1.0
N13 A:KXY1103 4.6 9.1 1.0
CG A:MET766 4.8 10.6 1.0
CB A:GLU762 4.8 13.6 0.5
C A:ILE759 4.8 9.8 1.0
O A:GLU762 4.8 9.6 1.0
CB A:GLU762 4.8 11.5 0.5
C A:ALA763 4.9 9.3 1.0
C17 A:KXY1103 5.0 10.8 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 16:24:03 2024

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