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dc.contributor.authorPerona, Almudena-
dc.contributor.authorRos, M. Piedad-
dc.contributor.authorMills, Alberto-
dc.contributor.authorMorreale, Antonio-
dc.contributor.authorGago, Federico-
dc.identifierdoi: 10.1007/s10822-020-00328-8-
dc.identifierissn: 1573-4951-
dc.identifier.citationJournal of Computer-Aided Molecular Design (2020)-
dc.description.abstractCetirizine, a major metabolite of hydroxyzine, became a marketed second-generation H antihistamine that is orally active and has a rapid onset of action, long duration of effects and a very good safety record at recommended doses. The approved drug is a racemic mixture of (S)-cetirizine and (R)-cetirizine, the latter being the levorotary enantiomer that also exists in the market as a third-generation, non-sedating and highly selective antihistamine. Both enantiomers bind tightly to the human histamine H receptor (hHR) and behave as inverse agonists but the affinity and residence time of (R)-cetirizine are greater than those of (S)-cetirizine. In blood plasma, cetirizine exists in the zwitterionic form and more than 90% of the circulating drug is bound to human serum albumin (HSA), which acts as an inactive reservoir. Independent X-ray crystallographic work has solved the structure of the hHR:doxepin complex and has identified two drug-binding sites for cetirizine on equine serum albumin (ESA). Given this background, we decided to model a membrane-embedded hHR in complex with either (R)- or (S)-cetirizine and also the complexes of both ESA and HSA with these two enantiomeric drugs to analyze possible differences in binding modes between enantiomers and also among targets. The ensuing molecular dynamics simulations in explicit solvent and additional computational chemistry calculations provided structural and energetic information about all of these complexes that is normally beyond current experimental possibilities. Overall, we found very good agreement between our binding energy estimates and extant biochemical and pharmacological evidence. A much higher degree of solvent exposure in the cetirizine-binding site(s) of HSA and ESA relative to the more occluded orthosteric binding site in hHR is translated into larger positional fluctuations and considerably lower affinities for these two nonspecific targets. Whereas it is demonstrated that the two known pockets in ESA provide enough stability for cetirizine binding, only one such site does so in HSA due to a number of amino acid replacements. At the histamine-binding site in hHR, the distinct interactions established between the phenyl and chlorophenyl moieties of the two enantiomers with the amino acids lining up the pocket and between their free carboxylates and Lys179 in the second extracellular loop account for the improved pharmacological profile of (R)-cetirizine.-
dc.description.sponsorshipFinancial support from the Spanish Ministry of Science and Innovation through grant SAF2015-64629-C2-2-R to F.G. is gratefully acknowledged-
dc.subjectG-protein coupled receptors-
dc.subjectBinding affinity-
dc.subjectMolecular dynamics simulations-
dc.subjectHuman serum albumi-
dc.titleDistinct binding of cetirizine enantiomers to human serum albumin and the human histamine receptor H1-
dc.contributor.funderMinisterio de Economía y Competitividad (España)-
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