title: Characterization of the species-dependent ketoprofen/albumin binding modes by induced CD spectroscopy and TD-DFT calculations.
abstract: The stereospecificity of high-affinity biorecognition phenomena at the basis of the activity of drugs is an important topic of active research in medicinal chemistry. The binding of drugs to their targets or to carrier proteins may lead to the onset of an induced circular dichroism (ICD) signal, which can be detected experimentally. Quantum mechanical (QM) calculations based on density functional theory (DFT) and its time-dependent formulation (TD-DFT) can be used to determine the theoretical chiroptical response of all the possible conformations of drugs bound to their hosts; by comparison with the experimental ICD spectra of drug-host complexes, this approach can lead to the identification of possible binding modes in the absence of X-ray crystallography or NMR data. The present article reports the application of experimental electronic circular dichroism (ECD) spectroscopy, DFT conformational analysis and TD-DFT calculations to the investigation of the binding modes of (S)-ketoprofen to serum albumins. The peculiar species-dependent ICD spectra observed for the binding of (S)-ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties inside the binding pocket. Such structural elucidations contribute to a better understanding of the changes in the pharmacokinetic and pharmacodynamic profiles of drugs among different species.
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, 40126 Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Tedesco
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, 40126 Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Pistolozzi
authors.affiliation: Department of Chemistry and Biology, University of Salerno, Via Giovanni Paolo II 132, Fisciano, 84084 Italy.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Zanasi
authors.affiliation: Department of Pharmacy and Biotechnology, University of Bologna, Via Belmeloro 6, Bologna, 40126 Italy. Electronic address: carlo.bertucci@unibo.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Bertucci
mesh_terms: D002942:Circular Dichroism / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D007660:Ketoprofen / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D012709:Serum Albumin / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: D012709:Serum Albumin; D007660:Ketoprofen
keywords: Conformational analysis; Density functional theory; Drug binding; Induced circular dichroism; Serum albumins