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Eur J Med Chem. 2014 Apr 22;77:91-5. doi: 10.1016/j.ejmech.2014.02.058. Epub 2014 Feb 28.

Novel insights on the structural determinants of clozapine and olanzapine multi-target binding profiles.

Author information

1
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.
2
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.
3
Center for Research in Molecular Medicine and Chronic Diseases (CIMUS), University of Santiago de Compostela, 15782, Spain.
4
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.

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.

KEYWORDS:

Antipsychotic drugs; Binding profile; GPCR; Molecular modelling; Multi-target; Site-directed mutagenesis

PMID:
24631727
DOI:
10.1016/j.ejmech.2014.02.058
[Indexed for MEDLINE]

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