A comprehensive computational analysis of cathinone and its metabolites using quantum mechanical approaches and docking studies

Struct Chem (2016) 27:1291–1302 DOI 10.1007/s11224-016-0779-9 ORIGINAL RESEARCH A comprehensive computational analysis of cathinone and its metabolites using quantum mechanical approaches and docking studies Wojciech Kolodziejczyk1,2 • Supratik Kar2 • Glake A. Hill2 • Jerzy Leszczynski2 Received: 3 May 2016 / Accepted: 22 May 2016 / Published online: 2 June 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com Abstract Conformers of the psychoactive compound of the Khat plant cathinone along with its amino alcohol metabolites norephedrine and norpseudoephedrine have been calculated using DFT (M062X/B3LYP) and MP2 levels of theory for gas and solution phases. Gas-phase studies revealed that cathinone has two, norephedrine has four and norpseudoephedrine has three low-energy conformations with all conformers connected by rotational transition states. To understand the solvent effect to the energetic profiles of the studied species, the conductor-like screening model is employed within aqueous medium. It explains lowering of energy of all studied conformers in solution. The molecular electrostatic potential surface data for each molecule revealed likely reaction sites for the studied molecules. The computed IR spectra for cathinone and its metabolites have been compared with experimental data and rotational transition states connecting all conformers have been reported. The natural bond orbital analyses for only ligands and separately for their complexes with amino acid residues in protein pockets from the docking results are also performed to corroborate the results obtained from the MP2 and DFT calculations. The comprehensive computational study explore important amino acid residues Electronic supplementary material The online version of this article (doi:10.1007/s11224-016-0779-9) contains supplementary material, which is available to authorized users. & Wojciech Kolodziejczyk 1 Department of Physical Chemistry, Wroclaw Medical University, ul. Borowska 211A, 50-556 Wroclaw, Poland 2 Interdisciplinary Center for Nanotoxicity, Department of Chemistry and Biochemistry, Jackson State University, 17910, 1400 J.R. Lynch Street, Jackson 39217, MS, USA and stabilizing energy of the studied molecules with the interacting proteins along with the reason behind the difference in potency for cathinone’s metabolites. Keywords Cathinone  DFT  Docking  Gaussian  MP2  Molecular electrostatic potential  NBO  Norephedrine  Norpseudoephedrine Introduction Cathinone, is a naturally occurring psychoactive substance obtained from the leaves of Khat (Catha edulis), an evergreen plant that grows at high attitudes in East Africa and Arabian Peninsula [1]. Cathinone is chemically b-ketoamphetamine, which can easily permeate the blood brain barrier (BBB) layer, causing sympathomimetic and psychostimulant actions by acting as a central nervous system (CNS) stimulant by promoting the release of monoamine neurotransmitters and likely inhibiting their uptake [2]. In recent years, cathinone and its derivatives are appeared in the illicit drugs market and these materials can be easily purchased from the internet at low cost [3]. Cathinone users report increased level of energy, a sensation of elation, and an enhanced imaginative ability similar to the effect of amphetamine [4]. Along with cathinone, other less potent stimulant substances are also present in khat leaves, namely norephedrine and norpseudoephedrine (cathinone) [5]. Taking into account the structural and pharmacological properties of amphetamine and cathinone, it can be concluded that they should act similarly by inducing dopamine releases from central dopaminergic nerve terminals, thus increasing the activity of dopaminergic pathways [6, 7]. Norephedrine or phenylpropanolamine (PPA) is a synthetic form of the ephedrine alkaloid that occurs naturally 123 1292 in plants of the genus Ephedra and one of the major metabolite of cathinone. It is generally used as a bronchodilator and also used as part of appetite suppressants. But, after a number of reported adverse effects (headache, intracranial, elevated blood pressure to cardiopulmonary arrest and even death), the FDA issued a public health warning to consumers; thus, PPA is no longer sold in USA without a prescription. In Canada, this drug ingredient was withdrawn from the market on 2001 [8]. However, in many countries PPA is still available, especially as a component of pharmaceutical products for the treatment of cold. Despite the extensive information about PPA toxicity, amazingly the number of scientific research is very scarce. Again, another metabolites of cathinone is L-norpseudoephedrine also referred as (-)-threo-b-hydroxyamphetamine, which is a psychostimulant drug of the amphetamine family. Similar to cathinone, L-norpseudoephedrine acts as a releasing agent of norepinephrine and to a lesser extent of dopamine [9]. Because of amphetamine-like effects and its resultant high abuse potential, cathinone and its metabolites were assigned Schedule I status by the US Drug Enforcement Administration (DEA) in 1993 and Class B status under the UK Misuse of Drugs Act in 1998 [10]. According to the American Association of Poison Control Centers report, 304 human exposure to bath salts calls across the country in 2010 and 6138 in 2011, representing a 2019 % increase within a 1-year span in the United States [11]. Drug Enforcement Administration (DEA) National Forensic Laboratory Information System also received an increase in reports of seizures due to cathinone and its derivatives, receiving 14 reports in 2009 from 8 states to 290 reports from 21 states in 2010 [10]. The patterns of usage of these derivatives are being tracked on the state level by the National Institute of Drug Abuse Community Epidemiology Work Group [12]. Similarly, in the European Union, data from the Early Warning System have reported a steady increase in the number of police and forensic cases related to synthetic cathinones since 2009. The Michigan Morbidity and Mortality 2012 weekly report stated that 46 % of bath salt users presenting to emergency rooms had comorbid mental illness, and 69 % had self-reported drug abuse [13]. In this present scenario, although few research exist on cathinone and its metabolic products [5, 14], there is still need for evaluation of chemical properties of cathinone and its chief metabolites. In this paper we reported conformational analysis, electronic structure, and thermodynamic properties of cathinone, norephedrine and norpseudoephedrine based on quantum chemical calculations and docking study. The molecular electrostatic potential surfaces (MEPS) of these molecules are also predicted. Based on the performed study, authors matched the probable 123 Struct Chem (2016) 27:1291–1302 metabolism pathway (Fig. 1) based on the work demonstrated by Brenneisen et al. [15]. With regard to the metabolic pathway published by Brenneis (...truncated)