ORIGINAL RESEARCH Modeling of dexmedetomidine conformers and their interactions with alpha2 adrenergic receptor subtypes Ramona F. Curpa ˘n 1 • Liliana Halip 1 • Ana Borota 1 • Maria Mracec 1 • Mircea Mracec 1 Received: 4 March 2015 / Accepted: 16 July 2015 Ó Springer Science+Business Media New York 2015 Abstract Dexmedetomidine (4-[(S)-1-(2,3-dimethyl-phenyl)- ethyl]-1H-imidazole), Dex, is potent agonist acting on a 2 - adrenergic receptors (a 2 -ARs). It can exist at the physio- logical 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 con- formational 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 a 2A -, a 2B -, and a 2C -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 imi- dazole 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. Keywords a 2 -Adrenergic receptor subtypes Á GPCR Á Conformational analysis Á PM3 Á HF/6-31G* Á Molecular docking Introduction Dexmedetomidine, Dex, is a selective agonist for a 2 -ARs (class A of G protein-coupled receptors (GPCR)) with neu- roprotective effects produced via the a 2A -adrenoceptor subtype [1]. Although the most significant side effects of Dex are hypotension and bradycardia, presently this drug is considered a safe and effective adjunct in various clinical applications including patients in operating room and in intensive care unit (ICU), postsurgical patients, and patients who need sedation or/and analgesia for invasive or nonin- vasive procedures. Dex has also shown efficacy in decreas- ing the need for opioids, benzodiazepines, propofol, and other sedative medications [2]. A series of reviews summa- rize the progress of studies on a 2 -AR subtype-mediated physiological and pharmacological actions [3], the agonists and antagonists targeting different a 2 -AR subtypes [4], and their use in clinical practice [5]. There are a large number of studies concerning the physiological and pharmacological effects of Dex, but to our knowledge, there are no studies regarding its possible active conformers, their number, and ionization states. This prompted us to perform conforma- tional and docking studies. Taking into account that Dex is an imidazole derivative and that in solution at physiological pH (pH 7.2–7.4) imidazole can exist in two forms: neutral (*62–72 % abundance) and protonated (*38–28 % abundance), both forms of Dex can compete for the binding sites of a 2 -AR subtypes. Present studies are performed for both ionization forms of Dex. The gas-phase geometries of Dex conformers obtained thorough conformational analysis Electronic supplementary material The online version of this article (doi:10.1007/s11224-015-0645-1) contains supplementary material, which is available to authorized users. & Liliana Halip lili.ostopovici@acad-icht.tm.edu.ro 1 Computational Chemistry Department, Institute of Chemistry Timisoara, Romanian Academy, 24 M. Viteazul Av., 300223 Timisoara, Romania 123 Struct Chem DOI 10.1007/s11224-015-0645-1