Screening derivatized peptide libraries for tight binding inhibitors to carbonic anhydrase II by electrospray ionization-mass spectrometry

Jinming Gao, Xueheng Cheng, Ruidan Chen, George B. Sigal, James E. Bruce, Brenda L. Schwartz, Steven A. Hofstadler, Gordon A. Anderson, Richard D. Smith, George M. Whitesides

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Abstract

This paper describes the use of electrospray ionization-mass spectrometry (ESI-MS) to screen two libraries of soluble compounds to search for tight binding inhibitors for carbonic anhydrase II (EC 4.2.1.1). The two libraries, H2NO2SC6H4C(O)NH-AA1-AA2-C(O)NHCH2CH2CO2H (1), where AA1 and AA2 are L-amino acids (library size: 289 compounds) or D-amino acids (256 compounds), were constructed by attaching tripeptides to the carboxyl group of 4-carboxybenzenesulfonamide. Screening of both libraries yielded, as the tightest binding inhibitor, compound 1 (AA, = AA2 = L-Leu; binding constant K(b) = 1.4 x 108 M-1). The ability of ESI-MS to estimate simultaneously the relative binding affinities of a protein to soluble ligands in a library, if general, should be useful in drug development.

Original languageEnglish (US)
Pages (from-to)1949-1955
Number of pages7
JournalJournal of Medicinal Chemistry
Volume39
Issue number10
DOIs
Publication statusPublished - May 10 1996

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ASJC Scopus subject areas

  • Organic Chemistry

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