Templates for design of inhibitors for serine proteases: Application of the program dock to the discovery of novel inhibitors for thrombin

Bioorganic and Medicinal Chemistry Letters

Volumn 8, Issue 18, 1998, Pages 2463-2466

  Massova, Irina ^a   Martin, Philip ^a   Bulychev, Alexey ^a   Kocz, Remek ^a   Doyle, Maureen ^a   Edwards, Brian F P ^a   Mobashery, Shahriar ^a  

^a WAYNE STATE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

SERINE PROTEINASE INHIBITOR; THROMBIN INHIBITOR;

ARTICLE; COMPUTER PROGRAM; CRYSTAL STRUCTURE; DRUG DESIGN; DRUG POTENCY; ENZYME ACTIVE SITE; ENZYME INHIBITION; ENZYME KINETICS; ENZYME STRUCTURE; X RAY CRYSTALLOGRAPHY;

BINDING SITES; DATABASES, FACTUAL; DRUG DESIGN; MODELS, CHEMICAL; MODELS, MOLECULAR; PROTEIN CONFORMATION; SERINE PROTEINASE INHIBITORS; SOFTWARE; TEMPLATES, GENETIC; THROMBIN;

EID: 17044457282     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(98)00444-2     Document Type: Article

References (23)

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15. 15. Compound 1 was made by the procedure of Brawner and Mertes (Brawner, S.; Mettes, K. B. J. Inorg. Nucl. Chem. 1979, 41, 764), compound 3 (phenylazoformic acid 2-phenylhydrazide) was purchased from the Aldrich Chemical Co., and compound 4 was synthesized according to the method of Beissel et al. (Beissel, T.; Della Vedova, B. S. P. C.; Wieghardt, K.; Boese, R. Inorg. Chem. 1990, 29, 1736).
16. 15. Compound 1 was made by the procedure of Brawner and Mertes (Brawner, S.; Mettes, K. B. J. Inorg. Nucl. Chem. 1979, 41, 764), compound 3 (phenylazoformic acid 2-phenylhydrazide) was purchased from the Aldrich Chemical Co., and compound 4 was synthesized according to the method of Beissel et al. (Beissel, T.; Della Vedova, B. S. P. C.; Wieghardt, K.; Boese, R. Inorg. Chem. 1990, 29, 1736).
17. 1) for compounds 1, 3, and 4 for α-thrombin were calculated by method of Dixon (Dixon, M. Biochem. J. 1953, 55, 170). A series of assay mixtures containing both Chromozym TH (Tosyl-Gly-Pro-Arg-4-nitranilide; Boehringer-Mannheim Co.) as the substrate (75 or 150 μM) and various concentrations of compounds 1, 3 and 4 as the inhibitor (0-175 μM for 1, 0-1250 μM for 3, and 0-800 μM for 4) were prepared in 50 mM Tris, 200 mM NaCl, 0.1 % polyethylene glycol (PEG; Sigma), pH 7.4, at 25 °C. Organic co-solvents (10%) were used, for compound 1 (DMSO) and for 3 and 4 (methanol). A portion of the enzyme was added to give a final concentration of 5 nM in a total volume of 0.1 mL. The enzyme activity was determined immediately.
18. 1) for compounds 1, 3, and 4 for α-thrombin were calculated by method of Dixon (Dixon, M. Biochem. J. 1953, 55, 170). A series of assay mixtures containing both Chromozym TH (Tosyl-Gly-Pro-Arg-4-nitranilide; Boehringer-Mannheim Co.) as the substrate (75 or 150 μM) and various concentrations of compounds 1, 3 and 4 as the inhibitor (0-175 μM for 1, 0-1250 μM for 3, and 0-800 μM for 4) were prepared in 50 mM Tris, 200 mM NaCl, 0.1 % polyethylene glycol (PEG; Sigma), pH 7.4, at 25 °C. Organic co-solvents (10%) were used, for compound 1 (DMSO) and for 3 and 4 (methanol). A portion of the enzyme was added to give a final concentration of 5 nM in a total volume of 0.1 mL. The enzyme activity was determined immediately.
19. free were 0.19 and 0.29, respectively, for 2σ data between 7.0 and 2.7 Å.
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