A theoretical study on the inclusion complexation of doxycycline with Crysmeb

Abstract The geometry of the inclusion complexes of 2-O-methyl-beta-cyclodextrin (called MeβCD or Crysmeb) with the two tautomers (enol and keto) isomer of doxycycline (DOX) in the gas phase, is determined using PM6 and ONIOM2 calculations with [B3LYP/6-31G(d):HF/3-21G*] level. Inclusion process pathways are described and the most probable structure of the 1:1 complex is sought through a potential energy scan using the PM6 method. Within the ONIOM2 procedure two levels of calculation are defined: B3LYP/6-31G(d) for DOX and the HF/3-21G* level for Meβ CD. The geometry of the most stable complex in the keto or enol forms obtained with the two methods, in which the aromatic ring is included inside the hydrophobic cavity of Crysmeb. The energetic differences between the two forms are 0.17 and 6.27 kcal/mol, respectively with PM6 and [B3LYP/6-31G(d):HF/3-21G*] calculations. These energies also include ZPE corrections. The energetically more favorable structure obtained with the ONIOM2 method leads to the formation of six intermolecular H-bonds between DOX and Crysmeb, i.e. three conventional H-bonds, one between the oxygen atom (O197) of the OH bond of DOX and the hydrogen atom (H140) of Crysmeb and the second between oxygen atom (O53) and a hydrogen atom (H218) of the hydroxyl group of DOX. The last one is between the oxygen atom (O73) and a hydrogen atom (H214) of the hydroxyl group of DOX. These H-bond are assisted by three weak H-bonds of type ( C-H ⋯ O ). All these interactions were investigated using the Natural Bond Orbital (NBO) approach.