Fluorine in PDB 7khh: Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide)

The structure of Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide), PDB code: 7khh was solved by J.M.Murray, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å)	68.38 / 2.28
Space group	P 31 2 1
Cell size a, b, c (Å), α, β, γ (°)	78.979, 78.979, 195.399, 90, 90, 120
R / Rfree (%)	17.8 / 22.9

The binding sites of Fluorine atom in the Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide) (pdb code 7khh). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 2 binding sites of Fluorine where determined in the Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide), PDB code: 7khh:
Jump to Fluorine binding site number: 1; 2;

Fluorine binding site 1 out of 2 in the Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide) within 5.0Å range: probe atom residue distance (Å) B Occ C:F301 b:36.9 occ:1.00 F78 C:WEP301 0.0 36.9 1.0 C75 C:WEP301 1.4 36.9 1.0 C74 C:WEP301 2.4 37.1 1.0 C76 C:WEP301 2.4 36.5 1.0 CE2 C:TYR98 3.1 40.9 1.0 CB D:ASP145 3.3 68.5 1.0 N D:ILE146 3.5 53.5 1.0 N77 C:WEP301 3.6 36.0 1.0 C73 C:WEP301 3.6 37.3 1.0 C D:ASP145 3.6 59.4 1.0 O16 C:WEP301 3.7 47.9 1.0 CD2 C:TYR98 3.8 40.4 1.0 CZ C:TYR98 3.8 41.5 1.0 O D:HOH243 3.9 48.8 1.0 SD D:MET149 3.9 37.9 1.0 CA D:ASP145 4.0 66.8 1.0 OH C:TYR98 4.0 42.4 1.0 CA D:ILE146 4.0 48.6 1.0 C72 C:WEP301 4.1 35.8 1.0 O D:ASP145 4.2 58.8 1.0 CB D:ILE146 4.3 46.4 1.0 CG D:ASP145 4.5 74.6 1.0 C13 C:WEP301 4.6 52.9 1.0 F79 C:WEP301 4.7 38.6 1.0 C15 C:WEP301 4.7 48.4 1.0 OD2 D:ASP145 4.7 77.8 1.0 N D:ASP145 4.8 72.5 1.0 CG C:TYR98 4.9 40.2 1.0 CD1 D:ILE146 4.9 45.7 1.0 CE1 C:TYR98 4.9 41.0 1.0

Fluorine binding site 2 out of 2 in the Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide)


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Ternary Complex of Vhl/BRD4-BD1/COMPOUND9 (4-(3,5-Difluoropyridin-2- Yl)-N-(11-(((S)-1-((2S,4R)-4-Hydroxy-2-((4-(4-Methylthiazol-5-Yl) Benzyl)Carbamoyl)Pyrrolidin-1-Yl)-3,3-Dimethyl-1-Oxobutan-2-Yl) Amino)-11-Oxoundecyl)-10-Methyl-7-((Methylsulfonyl)Methyl)-11-Oxo-3, 4,10,11-Tetrahydro-1H-1,4,10-Triazadibenzo[Cd,F]Azulene-6- Carboxamide) within 5.0Å range: probe atom residue distance (Å) B Occ C:F301 b:38.6 occ:1.00 F79 C:WEP301 0.0 38.6 1.0 C73 C:WEP301 1.3 37.3 1.0 C74 C:WEP301 2.3 37.1 1.0 C72 C:WEP301 2.4 35.8 1.0 C50 C:WEP301 2.7 34.3 1.0 C49 C:WEP301 2.9 35.3 1.0 N71 C:WEP301 2.9 34.2 1.0 CZ3 D:TRP81 2.9 41.7 1.0 CB D:PRO82 3.1 36.9 1.0 CH2 D:TRP81 3.2 42.0 1.0 C51 C:WEP301 3.3 33.2 1.0 CG D:PRO82 3.4 37.4 1.0 C48 C:WEP301 3.5 36.3 1.0 C75 C:WEP301 3.6 36.9 1.0 N77 C:WEP301 3.6 36.0 1.0 CE3 D:TRP81 3.7 40.7 1.0 C52 C:WEP301 3.9 34.5 1.0 C59 C:WEP301 4.1 31.0 1.0 C53 C:WEP301 4.1 36.1 1.0 C76 C:WEP301 4.1 36.5 1.0 CA D:PRO82 4.1 36.1 1.0 CZ2 D:TRP81 4.1 41.5 1.0 CD1 D:ILE146 4.1 45.7 1.0 O47 C:WEP301 4.3 38.1 1.0 C70 C:WEP301 4.4 32.7 1.0 C46 C:WEP301 4.4 37.3 1.0 C31 C:WEP301 4.5 42.6 1.0 CD2 D:TRP81 4.6 40.1 1.0 CD D:PRO82 4.6 36.5 1.0 N D:PRO82 4.6 37.0 1.0 F78 C:WEP301 4.7 36.9 1.0 C65 C:WEP301 4.7 31.0 1.0 CE2 D:TRP81 4.7 40.7 1.0 C60 C:WEP301 4.7 29.8 1.0 OH C:TYR98 4.9 42.4 1.0 C66 C:WEP301 4.9 31.6 1.0

P.S.Dragovich, T.H.Pillow, R.A.Blake, J.D.Sadowsky, E.Adaligil, P.Adhikari, J.Chen, N.Corr, J.Dela Cruz-Chuh, G.Del Rosario, A.Fullerton, S.J.Hartman, F.Jiang, S.Kaufman, T.Kleinheinz, K.R.Kozak, L.Liu, Y.Lu, M.M.Mulvihill, J.M.Murray, A.O'donohue, R.K.Rowntree, W.S.Sawyer, L.R.Staben, J.Wai, J.Wang, B.Wei, W.Wei, Z.Xu, H.Yao, S.F.Yu, D.Zhang, H.Zhang, S.Zhang, Y.Zhao, H.Zhou, X.Zhu. Antibody-Mediated Delivery of Chimeric BRD4 Degraders. Part 2: Improvement of in Vitro Antiproliferation Activity and in Vivo Antitumor Efficacy. J.Med.Chem. 2021.
ISSN: ISSN 0022-2623
PubMed: 33596073
DOI: 10.1021/ACS.JMEDCHEM.0C01846