Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures

Bioorganic and Medicinal Chemistry Letters

Volumn 20, Issue 6, 2010, Pages 1981-1984

  McLean, Larry R ^a   Zhang, Ying ^a   Degnen, William ^a   Peppard, Jane ^a   Cabel, Dasha ^b   Zou, Chao ^a   Tsay, Joseph T ^a   Subramaniam, Arun ^a   Vaz, Roy J ^a   Li, Yi ^a  

^a SANOFI   (France)

^b CAS Library Production Tucson   (United States)

Author keywords

DHODH; Dihydroorotate dehydrogenase inhibitor; Molecular docking; Virtual screening; X ray crystallographic structures

Indexed keywords

AMINOBENZOIC ACID DERIVATIVE; BREQUINAR; DIHYDROOROTATE DEHYDROGENASE; DIHYDROOROTATE DEHYDROGENASE INHIBITOR;

ARTICLE; BIOCHEMISTRY; CONTROLLED STUDY; CRYSTAL STRUCTURE; DRUG BINDING; DRUG SCREENING; DRUG STRUCTURE; DRUG SYNTHESIS; MOLECULAR DOCKING; PREDICTION; STRUCTURE ACTIVITY RELATION; X RAY CRYSTALLOGRAPHY;

CRYSTALLOGRAPHY, X-RAY; DRUG DISCOVERY; ENZYME INHIBITORS; MODELS, MOLECULAR; MOLECULAR STRUCTURE; OXIDOREDUCTASES ACTING ON CH-CH GROUP DONORS;

EID: 77649183272     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2010.01.115     Document Type: Article

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36. The assay method used for screening was based on that published by the group of Monika Loeffler et al. (Bader, B. et. al., Protein Expr. Purif. 1998, 13, 414 and Ref. 16), from whom the human DHODH was initially purchased. In this method, a blue indicator dye (2,3-dichlorophenolindo-phenol, DCIP) is substituted for the co-factor flavin normally found in the biological system. The DCIP turns from dark blue to clear during the course of the enzyme reaction and this can be monitored by absorbance at 600 nm. Since the reduced DCIP is eventually re-oxidized, a kinetic assay run over the first few minutes of the reaction was used for compound screening.
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38. Recombinant hDHODH was prepared essentially as described by Liu et al. (Ref. 32), with the inclusion of NV-10 to minimize aggregation. The protein was concentrated to 21 mg/mL in 50 mM Hepes, pH 7.7, 300 mM NaCl, 10% glycerol, and 10 mM N,N-dimethylundecylamine-N-oxide. Apo-crystals and co-crystals were obtained by hanging drop vapor diffusion by mixing equal volumes of protein and reservoir solution (2.4-2.5 M ammonium sulfate, 15% glycerol, 0.1 M sodium acetate, pH 5.0-5.2, 40 mM N,N-dimethylundecylamine-N-oxide, 20.8 mM N,N-dimethyldecylamine-N-oxide) at 25 °C. Data were collected either with a Rigaku R-Axis IV++ image plate and RU-H3R X-ray generator equipped with Xenocs Fox-2D optics or at the Advanced Photon Source (APS). Data were processed with HKL2000 and CNX. Molecular replacement (MOLREP) used 1D3G as starting structure. Coordinates have been deposited and are available from the PDB using accession code 3KVK (1), 3KVM (2), 3KVL (3), and 3KVJ (4).
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