title: Novel insights on the structural determinants of clozapine and olanzapine multi-target binding profiles.
abstract: The clinical efficacy of antipsychotic drugs has been associated with a certain binding profile for a set of G protein-coupled receptors (GPCR)s. In this work, we use the structurally-related clozapine-olanzapine pair to progress in the understanding of the structural properties that determine their divergent binding profiles and, thereby, their differing therapeutic efficacy. First, we present novel site-directed mutagenesis results that confirm our previous hypothesis on the importance of ligand interaction with positions 5.42 and 5.46 in transmembrane helix 5. Then, we use refined models of ligand-receptor complexes, built from recently published GPCR crystal structures, to gain further insight into the molecular mechanisms responsible for the observed experimental outcomes. In particular, we observe that preventing or potentiating hydrogen bonding with position 5.46, could allow obtaining ligands with, respectively, clozapine or olanzapine-like affinities. Results presented in this study could guide the design of antipsychotic candidates with tailored binding profiles.
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, E-08003 Barcelona, Spain. Electronic address: jana.selent@upf.edu.
authors.forename: Jana
authors.initials: J
authors.lastname: Selent
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, E-08003 Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Marti-Solano
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Rodríguez
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
authors.forename: Patricio
authors.initials: P
authors.lastname: Atanes
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Brea
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
authors.forename: Marian
authors.initials: M
authors.lastname: Castro
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, E-08003 Barcelona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Sanz
authors.affiliation: Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
authors.forename: M Isabel
authors.initials: MI
authors.lastname: Loza
authors.affiliation: Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Universitat Pompeu Fabra, IMIM (Hospital del Mar Medical Research Institute), Dr. Aiguader, 88, E-08003 Barcelona, Spain. Electronic address: manuel.pastor@upf.edu.
authors.forename: Manuel
authors.initials: M
authors.lastname: Pastor
mesh_terms: D014150:Antipsychotic Agents / Q000737:chemistry* / Q000494:pharmacology; D001569:Benzodiazepines / Q000737:chemistry* / Q000494:pharmacology; D001667:Binding, Competitive; D003024:Clozapine / Q000737:chemistry* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D000077152:Olanzapine; D011485:Protein Binding; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D008024:Ligands; D017448:Receptors, Dopamine D2; C113776:dopamine D2L receptor; D044282:Receptor, Serotonin, 5-HT1A; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine
keywords: Antipsychotic drugs; Binding profile; GPCR; Molecular modelling; Multi-target; Site-directed mutagenesis