Aromatic interactions impact ligand binding and function at serotonin 5-HT2C G protein-coupled receptors: receptor homology modelling,ligand docking,and molecular dynamics results validated by experimental studies |
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| Authors: | Tania Córdova-Sintjago Nancy Villa Lijuan Fang Raymond G. Booth |
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| Affiliation: | 1. Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USAtaniacsintjago@ufl.edu;3. Department of Medicinal Chemistry, University of Florida, Gainesville, FL, USA;4. Center for Drug Discovery, Northeastern University, Boston, MA, USA |
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| Abstract: | The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2 G protein-coupled receptor (GPCR) family consists of types 2A, 2B, and 2C that share ～75% transmembrane (TM) sequence identity. Agonists for 5-HT2C receptors are under development for psychoses; whereas, at 5-HT2A receptors, antipsychotic effects are associated with antagonists – in fact, 5-HT2A agonists can cause hallucinations and 5-HT2B agonists cause cardiotoxicity. It is known that 5-HT2A TM6 residues W6.48, F6.51, and F6.52 impact ligand binding and function; however, ligand interactions with these residues at the 5-HT2C receptor have not been reported. To predict and validate molecular determinants for 5-HT2C-specific activation, results from receptor homology modelling, ligand docking, and molecular dynamics simulation studies were compared with experimental results for ligand binding and function at wild type and W6.48A, F6.51A, and F6.52A point-mutated 5-HT2C receptors. |
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| Keywords: | Aromatic interactions serotonin 5-HT2C GPCR W6.48 F6.51 F6.52 homology modelling docking molecular dynamics drug design |
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