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Fluorine in PDB 6n0p: Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)

Enzymatic activity of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)

All present enzymatic activity of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254):
2.7.11.1;

Protein crystallography data

The structure of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254), PDB code: 6n0p was solved by M.Mamo, B.A.Appleton, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 46.56 / 2.37
Space group P 41 21 2
Cell size a, b, c (Å), α, β, γ (°) 93.130, 93.130, 166.690, 90.00, 90.00, 90.00
R / Rfree (%) 19.4 / 23.3

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) (pdb code 6n0p). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 6 binding sites of Fluorine where determined in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254), PDB code: 6n0p:
Jump to Fluorine binding site number: 1; 2; 3; 4; 5; 6;

Fluorine binding site 1 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 1 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F801

b:46.3
occ:1.00
 F30 A:K81801 0.0 46.3 1.0
C29 A:K81801 1.3 45.3 1.0
F33 A:K81801 2.2 41.7 1.0
F36 A:K81801 2.2 47.8 1.0
C27 A:K81801 2.4 44.8 1.0
N26 A:K81801 2.8 46.5 1.0
CD2 A:HIS574 3.2 31.4 1.0
C28 A:K81801 3.5 41.3 1.0
NE2 A:HIS574 3.6 31.3 1.0
CG A:HIS574 3.7 29.9 1.0
C25 A:K81801 4.0 44.7 1.0
O A:HOH1008 4.0 54.1 1.0
CE1 A:HIS574 4.2 31.0 1.0
CA A:HIS574 4.2 27.1 1.0
CD1 A:LEU567 4.2 26.1 1.0
ND1 A:HIS574 4.3 31.7 1.0
CB A:HIS574 4.4 27.0 1.0
C22 A:K81801 4.5 38.1 1.0
CG2 A:ILE572 4.6 25.9 1.0
O A:HIS574 4.7 32.8 1.0
C24 A:K81801 4.8 41.2 1.0
CB A:ASP594 4.9 29.0 1.0
O A:GLY593 4.9 25.2 1.0
C A:GLY593 4.9 27.9 1.0
CD2 A:LEU567 4.9 26.9 1.0
C A:HIS574 5.0 32.0 1.0

Fluorine binding site 2 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 2 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F801

b:41.7
occ:1.00
 F33 A:K81801 0.0 41.7 1.0
C29 A:K81801 1.4 45.3 1.0
F36 A:K81801 2.1 47.8 1.0
F30 A:K81801 2.2 46.3 1.0
C27 A:K81801 2.4 44.8 1.0
C28 A:K81801 2.8 41.3 1.0
N26 A:K81801 3.6 46.5 1.0
CA A:GLY593 3.9 23.2 1.0
CD2 A:HIS574 4.0 31.4 1.0
C A:GLY593 4.1 27.9 1.0
O A:ILE592 4.1 25.8 1.0
NE2 A:HIS574 4.2 31.3 1.0
C22 A:K81801 4.2 38.1 1.0
CD1 A:LEU567 4.2 26.1 1.0
N A:GLY593 4.3 22.7 1.0
C A:ILE592 4.4 28.0 1.0
O A:GLY593 4.4 25.2 1.0
CD2 A:LEU567 4.5 26.9 1.0
N A:ASP594 4.6 27.0 1.0
CG2 A:ILE592 4.6 26.9 1.0
CG2 A:ILE513 4.7 27.6 1.0
C25 A:K81801 4.7 44.7 1.0
O23 A:K81801 4.9 29.1 1.0

Fluorine binding site 3 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 3 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F801

b:47.8
occ:1.00
 F36 A:K81801 0.0 47.8 1.0
C29 A:K81801 1.3 45.3 1.0
F33 A:K81801 2.1 41.7 1.0
F30 A:K81801 2.2 46.3 1.0
C27 A:K81801 2.4 44.8 1.0
N26 A:K81801 3.1 46.5 1.0
C28 A:K81801 3.5 41.3 1.0
CD2 A:LEU567 3.7 26.9 1.0
CG1 A:VAL504 3.7 30.4 1.0
CG2 A:ILE572 4.0 25.9 1.0
CD1 A:LEU567 4.2 26.1 1.0
C25 A:K81801 4.4 44.7 1.0
CG A:LEU567 4.6 26.7 1.0
C22 A:K81801 4.7 38.1 1.0
O A:HOH1008 4.7 54.1 1.0
CG2 A:THR508 4.8 24.6 1.0
CD2 A:LEU505 4.9 33.4 1.0

Fluorine binding site 4 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 4 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 4 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F801

b:44.5
occ:1.00
 F30 B:K81801 0.0 44.5 1.0
C29 B:K81801 1.4 45.0 1.0
F33 B:K81801 2.1 41.1 1.0
F36 B:K81801 2.2 45.0 1.0
C27 B:K81801 2.4 48.1 1.0
N26 B:K81801 2.8 51.1 1.0
CD2 B:HIS574 3.5 24.4 1.0
C28 B:K81801 3.6 44.6 1.0
CG B:HIS574 3.9 23.0 1.0
NE2 B:HIS574 4.0 23.8 1.0
C25 B:K81801 4.1 49.1 1.0
CG2 B:ILE572 4.1 29.8 1.0
CA B:HIS574 4.1 21.4 1.0
CD1 B:LEU567 4.2 26.1 1.0
CB B:HIS574 4.4 21.1 1.0
CE1 B:HIS574 4.5 23.2 1.0
ND1 B:HIS574 4.5 23.9 1.0
O B:HIS574 4.6 24.9 1.0
C22 B:K81801 4.7 41.4 1.0
CG1 B:VAL504 4.7 30.2 1.0
CD2 B:LEU567 4.7 28.5 1.0
C B:HIS574 4.9 25.1 1.0
C24 B:K81801 4.9 45.2 1.0
N B:HIS574 5.0 22.5 1.0

Fluorine binding site 5 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 5 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 5 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F801

b:41.1
occ:1.00
 F33 B:K81801 0.0 41.1 1.0
C29 B:K81801 1.3 45.0 1.0
F36 B:K81801 2.1 45.0 1.0
F30 B:K81801 2.1 44.5 1.0
C27 B:K81801 2.4 48.1 1.0
C28 B:K81801 2.7 44.6 1.0
N26 B:K81801 3.6 51.1 1.0
CD2 B:HIS574 3.7 24.4 1.0
NE2 B:HIS574 3.8 23.8 1.0
CA B:GLY593 3.9 23.2 1.0
C B:GLY593 4.0 25.2 1.0
O B:GLY593 4.1 24.1 1.0
C22 B:K81801 4.1 41.4 1.0
CD1 B:LEU567 4.2 26.1 1.0
O B:ILE592 4.4 26.6 1.0
N B:GLY593 4.4 23.7 1.0
CG2 B:ILE592 4.5 27.6 1.0
C B:ILE592 4.5 27.7 1.0
N B:ASP594 4.6 21.8 1.0
CD2 B:LEU567 4.7 28.5 1.0
CG B:HIS574 4.7 23.0 1.0
C25 B:K81801 4.7 49.1 1.0
CE1 B:HIS574 4.8 23.2 1.0
O23 B:K81801 4.9 36.4 1.0
C24 B:K81801 5.0 45.2 1.0

Fluorine binding site 6 out of 6 in 6n0p

Go back to Fluorine Binding Sites List in 6n0p
Fluorine binding site 6 out of 6 in the Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 6 of Braf in Complex with N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4- Yl)-4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide (LXH254) within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F801

b:45.0
occ:1.00
 F36 B:K81801 0.0 45.0 1.0
C29 B:K81801 1.3 45.0 1.0
F33 B:K81801 2.1 41.1 1.0
F30 B:K81801 2.2 44.5 1.0
C27 B:K81801 2.4 48.1 1.0
N26 B:K81801 3.2 51.1 1.0
C28 B:K81801 3.3 44.6 1.0
CD2 B:LEU567 3.7 28.5 1.0
CG1 B:VAL504 3.9 30.2 1.0
CG2 B:ILE572 4.2 29.8 1.0
CD1 B:LEU567 4.3 26.1 1.0
C25 B:K81801 4.4 49.1 1.0
CD2 B:LEU505 4.5 31.0 1.0
C22 B:K81801 4.5 41.4 1.0
CG2 B:THR508 4.6 13.4 1.0
CG B:LEU567 4.7 27.0 1.0
CG2 B:ILE513 4.9 23.4 1.0

Reference:

S.Ramurthy, B.R.Taft, R.J.Aversa, P.A.Barsanti, M.T.Burger, Y.Lou, G.A.Nishiguchi, A.Rico, L.Setti, A.Smith, S.Subramanian, V.Tamez, H.Tanner, L.Wan, C.Hu, B.A.Appleton, M.Mamo, L.Tandeske, J.E.Tellew, S.Huang, Q.Yue, A.Chaudhary, H.Tian, R.Iyer, A.Q.Hassan, L.A.Mathews Griner, L.R.La Bonte, V.G.Cooke, A.Van Abbema, H.Merritt, K.Gampa, F.Feng, J.Yuan, Y.Mishina, Y.Wang, J.R.Haling, S.Vaziri, M.Hekmat-Nejad, V.Polyakov, R.Zang, V.Sethuraman, P.Amiri, M.Singh, W.R.Sellers, E.Lees, W.Shao, M.P.Dillon, D.D.Stuart. Design and Discovery of N-(3-(2-(2-Hydroxyethoxy)-6-Morpholinopyridin-4-Yl) -4-Methylphenyl)-2-(Trifluoromethyl)Isonicotinamide, A Selective, Efficacious, and Well-Tolerated Raf Inhibitor Targeting Ras Mutant Cancers: the Path to the Clinic. J.Med.Chem. 2019.
ISSN: ISSN 0022-2623
PubMed: 31059256
DOI: 10.1021/ACS.JMEDCHEM.9B00161
Page generated: Thu Aug 1 22:25:28 2024

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