Benzenesulfonamide-peptide conjugates as probes for secondary binding sites near the active site of carbonic anhydrase

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 5, 1996, Pages 559-564

  Sigal, George B ^a   Whitesides, George M ^a  

^a HARVARD UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZENESULFONAMIDE DERIVATIVE; CARBONATE DEHYDRATASE; PEPTIDE DERIVATIVE;

ARTICLE; BINDING SITE; ENZYME ACTIVE SITE; ENZYME BINDING; ENZYME INHIBITION;

EID: 0029925009     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/0960-894X(96)00069-8     Document Type: Article

References (14)

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2. Jain, A.; Huang, S. G.; Whitesides, G. M. J. Am. Chem. Soc. 1994, 116, 5057.
3. Cappalonga, A. M.; Alexander, R. S.; Christianson, D. W. J. Am. Chem. Soc. 1994, 116, 5063.
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6. 6) δ 170.01, 169.71, 169.21, 166.31, 165.60, 146.40, 136.85, 128.09, 125.61, 42.72, 41.73, 38.23, 25.46.
7. n-NHS (2 μmol) in 50 μL of DMF was added to an aq solution containing the AA (5 μmol) and sodium bicarbonate (25 μmol. The resulting solution was incubated for 24 h at room temperature.
8. Chen, R. F.; Kernohan, J. C. J. Biol. Chem. 1967, 242, 5813.
9. + 486.1644.
10. Richards, F. M. Annu. Rev. Biophys. Bioeng. 1977, 6, 151
11. Radzicka, A.; Wolfenden, R. Biochemistry 1988, 27, 1664.
12. Kamlet, M. J.; Doherty, R. M.; Abraham, M. H.; Marcus, Y.; Taft, R. W. J. Phys. Chem. 1988, 92, 5244.
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14. Alternatively, the difficulty in finding polar secondary binding elements could be ascribed to the tendency of the peptide chains to associate with the hydrophobic face of the active site (ref 2 and 3). By analogy to the known structure of SB-benzylamide in the active site, we predict that the terminal amino acids of inhibitors of the form SB-Phe-AA will be directed toward the hydrophilic side of the active site (we base this prediction on the assumption that the SB group and aromatic side-chain of SB-Phe-AA will occupy roughly the same locations as determined for SB-benzylamide). In particular, molecular modeling predicts that SB-Phe-Gly, SB-Phe-Asn, and SB-Phe-Asp should be in close enough proximity to Asn 63, Asn 68 and Gln 93 in the CA active site to form hydrogen bonds with some or all of these amino acids. We synthesized these inhibitors and tested them for binding. Despite the fact that the polar groups should be capable of forming hydrogen bonds with polar groups on the hydrophilic side of the active site, the more polar side-chains led to decreased binding ability.