Screening Derivatized Peptide Libraries for Tight Binding Inhibitors to Carbonic Anhydrase II by Electrospray Ionization-Mass Spectrometry
journal contributionposted on 1996-05-10, 00:00 authored by 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
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 188.8.131.52). 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 (AA1 = AA2 = l-Leu; binding constant Kb = 1.4 × 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.