Binding modes of drug-albumin complexes investigated by induced CD spectroscopy and TD-DFT calculations

At the molecular level, the activity of drugs relies on a sequence of biorecognition phenomena, such as the binding to biological macromolecules, which define their pharmacological, toxicological and pharmacokinetic profiles. Physiologically-relevant interactions are usually very stereospecific: the occurrence of high binding affinities for specific stereochemical configurations or conformational arrangements of a drug is a very important research topic in the field of medicinal chemistry. When a drug is bound with high affinity to its target or to a carrier protein, e.g. a serum albumin, the conformational restraint due to the interaction may result in the insurgence of induced circular dichroism (ICD), which can be detected experimentally by spectroscopic analysis: nice examples are given by the ICD spectra of diazepam and ketoprofen complexed with human serum albumin (HSA). [1] Quantum mechanical (QM) calculations based on time-dependent density functional theory (TD-DFT) can be used to investigate the theoretical ICD spectra of all the possible conformational arrangements of the ligand, and may result very helpful in the identification of possible binding modes. [2] The present communication will report the application of TD-DFT calculations to the investigation of the binding modes of ketoprofen and benzodiazepines to serum albumins: in particular, the stereospecific binding of the M conformation of benzodiazepines to HSA is confirmed, and the peculiar species-dependent ICD spectra observed for the binding of ketoprofen to different serum albumins can be explained by the selection of different mutual arrangements of the phenyl moieties in the binding pockets. [1] M. Pistolozzi, C. Bertucci, Chirality 20, 552 (2008). [2] S. Ionescu, I. Matei, C. Tablet, M. Hillebrand, Phys. Chem. Chem. Phys. 15, 11604 (2013).