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Modeling of dexmedetomidine conformers and their interactions with alpha2 adrenergic receptor subtypes

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Abstract

Dexmedetomidine (4-[(S)-1-(2,3-dimethyl-phenyl)-ethyl]-1H-imidazole), Dex, is potent agonist acting on α2-adrenergic receptors (α2-ARs). It can exist at the physiological pH in both forms: neutral and protonated. The results of receptor-independent and receptor-dependent studies applied to both forms of Dex are reported. A conformational analysis with PM3 semiempirical MO and ab initio HF/6-31G* methods was carried out for both forms of Dex. The calculated geometries of low-energy conformers of Dex were compared with X-ray geometry and those of conformers resulted from molecular docking of Dex in the binding pockets of 3D homology models of the α2A-, α2B-, and α2C-adrenoceptor subtypes. A MM/QM (molecular mechanics/quantum mechanics) docking study was performed to refine and optimize receptor–ligand complex and close contacts between the ligand and amino acids lining the binding cavity. Two-dimensional potential energy surface and docking results suggest that the imidazole ring can easily adopt the best orientation for an efficient interaction with the carboxylate group of Asp3.32 from the binding cavity of alpha2 adrenergic receptor subtypes.

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Acknowledgments

This work was supported by CNCSIS-UEFISCSU, project number PN-II-PCE-ID 1268/2007.

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Authors and Affiliations

  1. Computational Chemistry Department, Institute of Chemistry Timisoara, Romanian Academy, 24 M. Viteazul Av., 300223, Timisoara, Romania

    Ramona F. Curpăn, Liliana Halip, Ana Borota, Maria Mracec & Mircea Mracec

Authors
  1. Ramona F. Curpăn
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  2. Liliana Halip
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  3. Ana Borota
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  4. Maria Mracec
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  5. Mircea Mracec
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Correspondence to Liliana Halip.

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Curpăn, R.F., Halip, L., Borota, A. et al. Modeling of dexmedetomidine conformers and their interactions with alpha2 adrenergic receptor subtypes. Struct Chem 27, 871–881 (2016). https://doi.org/10.1007/s11224-015-0645-1

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  • DOI: https://doi.org/10.1007/s11224-015-0645-1

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