Induced circular dichroism of drug-albumin complexes: characterization of binding modes by quantum chemical calculations

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, contributing to the design and development of new potent and selective drugs. The binding of drugs to their targets may lead to the onset of an induced circular dichroism (ICD) signal, which can be detected experimentally (Figure 1). ICD spectroscopy, therefore, provides versatile and useful methods for characterizing the structural and dynamic properties of the binding of drugs to target proteins. [1] Within this framework, the combined application of experimental ICD spectroscopy and quantum chemical (QC) calculations based on density functional theory (DFT) and its time-dependent formulation (TD-DFT) is a recently emerging approach which allows to identify the conformational features of ligands bound to target proteins even in the absence of a detailed structure of the binding sites, either obtained from experimental X-ray crystallography and NMR measurements or from computational models of the complex. [2] QC methods can be used to determine the theoretical chiroptical responses of all the possible conformations of drugs bound to their hosts and compare them with the experimental ICD spectra of drug–host complexes. For instance, the peculiar species-dependent ICD spectra observed for the binding of (S)-ketoprofen to different serum albumins could be explained by the selection of different mutual arrangements of the phenyl moieties inside the binding pocket, contributing to a better understanding of the changes in the pharmacokinetic and pharmacodynamic profiles of drugs among different species. [3] Further applications of this combined ICD/QC approach to the characterization of the binding modes of known ligands for the high-affinity binding sites of human serum albumin (HSA) will be reported, namely for pyrazolidine-3,5-diones and benzodiazepines, which are frequently used as ICD binding markers for Sudlow’s site I and site II, respectively. [1] 1. Tedesco, D.; Bertucci, C. Induced circular dichroism as a tool to investigate the binding of drugs to carrier proteins: Classic approaches and new trends. J. Pharm. Biomed. Anal. 2015, in press, doi: 10.1016/j.jpba.2015.02.024. 2. Ionescu, S.; Matei, I.; Tablet, C.; Hillebrand, M. Theoretical ECD calculations – a useful tool for estimating the conformational change of a ligand in the binding pocket of proteins. Phys. Chem. Chem. Phys. 2013, 15, 11604-14. 3. Tedesco, D.; Pistolozzi, M.; Zanasi, R.; Bertucci, C. Characterization of the species-dependent ketoprofen/albumin binding modes by induced CD spectroscopy and TD-DFT calculations. J. Pharm. Biomed. Anal. 2015, in press, doi: 10.1016/j.jpba.2014.11.029.