Screening derivatized peptide libraries for tight binding inhibitors to carbonic anhydrase II by electrospray ionization-mass spectrometry.
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 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 x 10(8) 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.
Gao
J
J
Department of Chemistry, Harvard University, Cambridge, Massachusetts 02138, USA.
Cheng
X
X
Chen
R
R
Sigal
G B
GB
Bruce
J E
JE
Schwartz
B L
BL
Hofstadler
S A
SA
Anderson
G A
GA
Smith
R D
RD
Whitesides
G M
GM
D000595:Amino Acid Sequence; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects*; D005583:Fourier Analysis; D013058:Mass Spectrometry / Q000379:methods*; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
D002257:Carbonic Anhydrase Inhibitors; D010455:Peptides; D002256:Carbonic Anhydrases