Bicyclic carbamates as inhibitors of papain-like cathepsin proteases

Bioorganic and Medicinal Chemistry Letters

Volumn 17, Issue 5, 2007, Pages 1254-1259

  Epple, Robert ^a   Urbina, Hugo D ^a   Russo, Ross ^a   Liu, Hong ^a   Mason, Daniel ^a   Bursulaya, Badry ^a   Tumanut, Christine ^a   Li, Jun ^a   Harris, Jennifer L ^a  

^a GENOMICS INSTITUTE OF THE NOVARTIS RESEARCH FOUNDATION   (United States)

Author keywords

Carbamates; Cathepsins; Protease inhibitors

Indexed keywords

CARBAMIC ACID DERIVATIVE; CARBONYL DERIVATIVE; CYSTEINE PROTEINASE; NITROGEN; PAPAIN; PIPERIDINE DERIVATIVE; PROTEINASE INHIBITOR; THIOL GROUP; URETHAN;

ARTICLE; CALCULATION; COMPUTER MODEL; COVALENT BOND; DRUG POTENCY; DRUG SYNTHESIS; HYDROLYSIS; PROTEIN DEGRADATION;

BICYCLO COMPOUNDS, HETEROCYCLIC; BINDING SITES; CARBAMATES; CATHEPSINS; COMPUTATIONAL BIOLOGY; ELECTRONS; MODELS, MOLECULAR; PAPAIN; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33846895217     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.bmcl.2006.12.014     Document Type: Article

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23. Detailed synthetic procedures to compounds 3-21 can be found in Supplementary material.
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27. ** basis set and hybrid DFT functional B3LYP were employed. The aqueous solvation was treated with the Poisson-Boltzmann continuum-dielectric method.
28. 50 = 1 nM) or DMSO (control) for 60 min at 37 °C with slow agitation on a shaker. Inhibition of the enzymatic activity was monitored according to the enzyme inhibition assay described in reference 24, by adding 50 μL of the preincubated enzyme-inhibitor mixture into 50 μL of 200 μM fluorogenic peptide substrate Ac-His-Pro-Val-Lys-ACMA. Alternatively, the enzyme-inhibitor mixture was injected into a 3-mL SlideDialyzer (Pierce, 7500-kDa cutoff) and dialyzed at 4 °C against 1 L of dialysis buffer (100 mM NaOAc, pH 5.5, 100 mM NaCl, 1 mM EDTA, 0.001% Brij-35, and 2 mM DTT). The dialysis buffer was changed three times in 8 h intervals. After dialysis, the cathepsin B activity was assayed as described above.
29. 2. Trypsin was added to the sample and proteolysis was carried out at 37 °C for 4 h. Then chymotrypsin was added and the reaction was continued at rt for another 18 h.
30. Procedures and results for the mass spectrometric analysis of the cathepsin B digests can be found in Supplementary material.
31. Procedures and results for the temperature-dependent metabolite monitoring can be found in Supplementary material.
32. To model the interaction of the cyclic carbamates with cathepsin B, we used a mixed Monte Carlo Multiple Minimum (MCMM)/LLMOD (Large Scale LowMode) conformational search strategy available in MacroModel (version 8.0; Schrodinger, Inc.). The structural perturbation via the LLMOD method is alternated with the random changes in torsion angles from the MCMM method. During the LLMOD structural perturbation, protein residues within 4 Å from the bound ligand were allowed to move freely. The inhibitor was subjected to perturbations via TORS command available in MacroModel. The employed force field was OPLS-AA 2005 with distance-dependent dielectric constant 2r and no explicit solvation.
33. The free energy of binding of compounds was obtained by subtracting the ligand and receptor energies from that of the complex. For the free energy calculations an OPLS-AA force field (Macromodel, Schrodinger Inc.) was employed and the solvation was accounted for via Generalized Born method.