کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1398968 | 1501139 | 2014 | 5 صفحه PDF | دانلود رایگان |
• New GPCR structures and site-directed mutagenesis yield new drug binding models.
• Binding profiles of clozapine and olanzapine are related to interaction with H5.
• Hydrogen bonding with position 5.42 and 5.46 would favor an olanzapine profile.
• Conversely, a hydrophobic interaction with 5.46 would favor a clozapine profile.
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.
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Journal: European Journal of Medicinal Chemistry - Volume 77, 22 April 2014, Pages 91–95