N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S: In silico design,synthesis and biochemical characterization |
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| Affiliation: | 1. Pharmaceutical Institute, Pharmaceutical and Medicinal Chemistry, University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany;2. Bonn Aachen International Center for Information Technology BIT, Life Science Informatics, University of Bonn, Endenicher Allee 19c, D-53115 Bonn, Germany;3. Instituto de Química de Sao Carlos, University of Sao Paulo, Avenida Trabalhador Sancarlense 400, BR-13560-970 Sao Carlos, Brazil;4. Department of Natural Sciences, University of Applied Sciences Bonn-Rhein-Sieg, von-Liebig-Str. 20, D-53359 Rheinbach, Germany;1. Department of Organic and Medicinal Chemistry, Faculty of Pharmacy, University of Seville, E-41071 Seville, Spain;2. Clinical Unit of Infectious Diseases, Microbiology, and Preventive Medicine, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain;3. Institute of Biomedicine of Seville, University Hospital Virgen del Rocío, CSIC, University of Seville, Seville, Spain;4. Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende (CS), Italy;5. Department of Medicine, University of Seville, Seville, Spain;1. Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA;2. Edison Biotechnology Institute, Ohio University, Athens, OH 45701, USA;3. Department of Biomedical Science, Ohio University, Athens, OH 45701, USA;4. Program of Molecular and Cellular Biology, Ohio University, Athens, OH 45701, USA;1. Istituto Pasteur Italia – Fondazione Cenci Bolognetti, Department of Biology and Biotechnology ‘Charles Darwin’, University of Rome “Sapienza”, 00185 Rome, Italy;2. Department of Chemistry, University of Rome “Sapienza”, 00185 Rome, Italy;3. Oncogenomic and Epigenetic Unit, Regina Elena National Cancer Institute, 00144 Rome, Italy;4. Department of Research, Advanced Diagnostic, and Technological Innovation, Regina Elena National Cancer Institute, 00144 Rome, Italy;1. Univ. Orléans, CNRS, ICOA, UMR 7311, F-45067, Orléans, France;2. INSERM, UMR 1100, Pathologies Respiratoires: protéolyse et aérosolthérapie, Centre d’Etude des Pathologies Respiratoires, Université François Rabelais, F-37032, Tours Cedex, France;3. Medicinal Chemistry Department, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland |
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| Abstract: | A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Ki = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4′-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Ki = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S. |
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| Keywords: | Cathepsin S Nitriles Reversible inhibition Sulfonamides |
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