Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
2485287 | Journal of Pharmaceutical Sciences | 2011 | 9 Pages |
Abstract
Daptomycin is a cyclic lipopeptide antibiotic. The ionization constants of daptomycin have not been individually elucidated. The objective of this research is to determine the sequenceâspecific ionization constants of daptomycin in the monomeric state. The pH titrations of daptomycin were performed by nuclear magnetic resonance (NMR) spectroscopy. The sequenceâspecific pKa values for the four acidic residues and one aromatic amine (Kynâ13) in daptomycin were determined by twoâdimensional total correlation spectroscopy 1H NMR. From the NMR pH titration, the estimated pKa values for Aspâ3, Aspâ9, and methylglutamic acid (mGluâ12) were determined to be 4.2, 3.8, and 4.6 in the absence of salt, and 4.1, 3.8, and 4.4 in the presence of 150 mM NaCl, respectively. The pKa value for Aspâ7 is estimated to be approximately 1.0 in the absence of salt and 1.3 in the presence of salt. The estimated Hill coefficients for Aspâ7 were 0.72 and 1.31 in the absence and presence of salt, respectively. The increase in Hill coefficients from 0.72 to 1.31 with increasing salt concentration is consistent with the estimated lower pKa in the absence of salt, and suggests that a salt bridge is formed in solution possibly between Aspâ7 acidic group and the neighboring Ornâ6 basic group. © 2011 WileyâLiss, Inc. and the American Pharmacists Association J Pharm Sci 100:4225-4233, 2011
Keywords
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Pharmacology, Toxicology and Pharmaceutical Science
Drug Discovery
Authors
Jiang Qiu, Liping Yu, Lee E. Kirsch,