Theoretical study of the inclusion processes of Venlafaxine with b-cyclodextrin O. Attoui Yahia a, * , D.E. Khatmi b a Department of Chemistry, Faculty of Science, Badji-Mokhtar University, BP. 12 Annaba, Algeria b Department of Chemistry, Faculty of Science, Guelma’s University, Algeria article info Article history: Received 20 April 2009 Received in revised form 25 May 2009 Accepted 1 June 2009 Available online 10 June 2009 Keywords: Cyclodextrin Venlafaxine PM3 ONIOM NBO abstract Geometry optimizations of Venlafaxine/b-Cyclodextrin complex were carried out using MM2, PM3, ONI- OM2 and ONIOM3 methods. The binding and complexation energies for both orientations considered in this research are reported. The geometry of the most stable complex shows that the aromatic ring is dee- ply self-included inside the hydrophobic cavity of b-CD also an intermolecular hydrogen bond is estab- lished between host and guest molecules. This suggests that hydrophobic effect and hydrogen bond play an important role in the complexation process. Additional information about binding in the com- plexes (C1) and (D1) was obtained by NBO analysis, the stabilization energy E (2) calculated with ONIOM3 method is more significant. Ó 2009 Elsevier B.V. All rights reserved. 1. Introduction The Venlafaxine whose commercial name is ‘‘EFFEXOR”, is a new family of antidepressant, widely used in the treatment of the anxiety. It acts like a fast inhibitor selective of Serotonin and noradrenaline for the neurotransmitters receptor. Its solubility in water is 572 mg/ml [1]. Cyclodextrins (CDs) are water-soluble oli- gosaccharides composed of 6 (a), 7 (b) and 8 (c) units of -D-(+) glu- copyranose units arranged in a truncated cone-shaped structure as shown in Fig. 1. They are obtained by enzymatic degradation of the starch. All the polar groups are located at the exterior and the cav- ity is relatively hydrophobic [2–5]. This allows the formation of the inclusion complex by admitting inside the cavity one or more in- vited molecules without to establish of covalent bond. In order to increase their solubility and to study their possibility to use in complex form; Mamora et al. have prepared their inclu- sion complex with b-cyclodextrin [6]. According this study based on NMR observations they confirm the formation of 1:1 inclusion complex in solution and propose a mode of inclusion through the primary phase in which the phenyl ring of Venlafaxine is entirely embedded inside of the cavity. The authors displayed within their article a very imprecise geo- metrical form in which one distinguish only a phenyl ring inside the geometrical shape of a cone and the rest of the molecule re- mains outside the cone. The geometrical form was proposed using 1 H NMR spectroscopy [6]. However, as we see it the results obtained from 1 H NMR spec- troscopy are not enough to elucidate completely the geometry of the complex and to describe the nature of intermolecular binding. So to complement these results, theoretical studies based on molecular modelling must be carried out to give a definitive pic- ture to the inclusion complex. The agreement between theoretical results and experimental data can be a potent way to determine the geometry of supramo- lecular system [7]. The progress on computational chemistry over the past decades has permitted to reach a high degree of accuracy, as well as the possibility of investigating systems with increasing size. However, the investigation of large molecular systems is limited by the re- quired computational effort and the precision of the used method. The use of the calculations methods such ab-initio or DFT on the totality of the inclusion complex will be computationally time- expensive because this system consists of 194 atoms. Therefore it appears a promising field to use a hybrid ONIOM [8–10] method to perform a geometry optimization especially that is known that under certain circumstances the CD provides only an environment effect. In this method we have applied a various levels of calculations on different parts of the system. This decreases considerably the computing time without any simplifications on the model. Accord- ing to our knowledge this method was rarely used for these systems and the literature is limited only at very few examples [11–15]. So, it appears a promising field to use ONIOM method to study the chemistry of CD’s complexes. This study was carried out with the aim to propose a more precise 3D structure of this inclusion complex, to quantify the 0166-1280/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.theochem.2009.06.007 * Corresponding author. E-mail address: waschem2006@yahoo.fr (O. Attoui Yahia). Journal of Molecular Structure: THEOCHEM 912 (2009) 38–43 Contents lists available at ScienceDirect Journal of Molecular Structure: THEOCHEM journal homepage: www.elsevier.com/locate/theochem