Non-covalent interactions between sertraline stereoisomers and 2-hydroxypropyl-β-cyclodextrin: a quantum chemistry analysis

Abstract

Inclusion compounds formed between sertraline stereoisomers and β-cyclodextrin, and 2-hydroxypropyl-β-cyclodextrin, were analyzed by using quantum chemistry methods. The exploration of the potential energy surface was performed using chemical intuition and classical molecular mechanics. This approach delivered around 200 candidates for low energy adducts, which were optimized through the PBE0/6-31G(d,p) method, and after this process solvent effects were considered by the continuous solvent model. This analysis showed that β-cyclodextrin and 2-hydroxypropyl-β-cyclodextrin are good trappers of sertraline, although the isomers suggested by molecular dynamics presented higher binding energies than those obtained by chemical intuition. The role of hydrogen bonds in the formation of adducts was studied using the non-covalent interactions index and the quantum theory of atoms in molecules. In this article we concluded that these interactions are present in all adducts, however, they are not important in the stabilization of these inclusion compounds. The molecular electrostatic potential indicates that Coulomb interactions could be responsible for the formation of these systems, although sophisticated solvent models must be used to confirm this conclusion, which are impractical in this case because of the sizes involved in these systems.

Fig. 1. Sertraline stereoisomers: (I) cis-(1S,4S), (II) cis-(1R,4R), (III) trans-(1R,4S), (IV) trans-(1S,4R).

Fig. 2. Two views of (a) β-cyclodextrin and (b) 2-hydroxypropyl-β-cyclodextrin. Both structures were optimized with the PBE0/6-31G(d,p) method.

Fig. 3. Schematic representation of geometries of inclusion compounds formed between βCD and sertraline stereoisomer I proposed by chemical intuition .

Fig. 4. Three lowest-lying βCD:I adducts obtained from proposals made by chemical intuition (CI) and molecular dynamics (MD). Final structures obtained with the PBE0/6-31G(d,p) method.

Fig. 5. Electron density with an isosurface of 0.01 atomic units, in white for βCD and orange for SRT stereoisomer I. Non-covalent interaction index shown as green (weak interactions) and blue (strong interactions) isosurfaces.

Fig. 6. Three lowest-lying HPβCD:I adducts obtained from chemical intuition (CI) and molecular dynamics (MD). Final structures were obtained with the PBE0/6-31G(d,p) method.

Fig. 7. Electron density (ρ(r) = 0.01 atomic units), in white for HPβCD and orange for SRT stereoisomer I. Non-covalent interaction index shown as green (weak interactions) and blue (strong interactions) isosurfaces. Both isomers were suggested by molecular dynamics (MD).

Fig. 8. Conformation of the most stable geometries of inclusion compounds formed between HPβCD and three stereoisomers of sertraline: (II) cis-(1R,4R), (III) trans-(1R,4S) and (IV) trans-(1S,4R).

Fig. 9. Electron density with an isosurface of 0.01 atomic units, in white for HPβCD and orange for SRT. Non-covalent interaction index shown as green (weak interactions) and blue (strong interactions) isosurfaces.

Fig. 10. Molecular electrostatic potential of HPβCD from −0.07 (blue color) to 0.07 (red color) atomic units mapped over an isosurface of the electron density (ρ(r) = 0.01 atomic units).

Fig. 11. Molecular electrostatic potentials of the four stereoisomers of sertraline from 0.00 (blue color) to 0.16 (red color) atomic units over an isosurface of the electron density (ρ(r) = 0.01 atomic units).