Molecular modelling of the inclusion complexes between β‐cyclodextrin and (R)/(S)‐methylphenobarbitone and its application to HPLC

Abstract

Molecular modelling of beta-cyclodextrin and optimisation of its potential energy suggests that a favoured conformation is that distorted from a symmetrical torus. The inclusion of water molecules into the torus cavity simulates the increased stability in an aqueous solvent. Complexes of beta-cyclodextrin with (R)- and (S)-enantiomers of methylphenobarbitone have been modelled and energetically optimised by the application of molecular mechanics. The simulations suggests that the guest molecules adopt an orientation in which the phenyl ring is projected into the torus cavity, with in each case the plane of the ring parallel to a longer axis of the distorted torus and slightly displaced from the axis through the torus cavity. It is suggested that the asymmetry in the macrocyclic ring contributes to chiral recognition as a result of additional discriminatory binding to the barbiturate ring residue of each enantiomer, which occupy different 3D geometries. The enantiomers form complexes of different minimum potential energies. The resulting difference in complex stability can be related to the behaviour of beta-cyclodextrin, as a mobile phase additive in reverse-phase HPLC to effect chiral separation of rac-methylphenobarbitone during chromatography.

A novel synthetic luteinizing hormone-releasing hormone (LHRH) analogue coupled with modified β-cyclodextrin: Insight into its intramolecular interactions

“…To our knowledge the cavity of β-CD can host only one aromatic ring [46][47][48][49]. In our results the Trp and Tyr protons show inter-segment NOEs of similar intensity.…”

Comparison of cyclodextrin-barbiturate noncovalent complexes using electrospray ionization mass spectrometry and capillary electrophoresis

“…11 Thus studies have been attempted using X-ray crystal structure analysis and molecular modeling 12 and used to generate empirical threedimensional structures of solution state complexes. 9,13 Although these molecular mechanics approach have produced some interesting results, it is inherently very complicated in nature and cannot be applied for the simple and routine study of the complex formation phenomenon. In addition, the above approaches do not effectively account for hydrophobic interactions and the effect of pH and buffer ionic strength in complex formation.…”

“…Kobor et al 8 combined these studies with molecular modeling to study chiral recognition in GC of limolene and 1-phenylethanol. Durham and Liang 9 have modelled inclusion complexes between methyl phenobarbital and b-cyclodextrin (b-CD) and studied the stability in an aqueous mobile phase by energy minimizations on cyclodextrin along with water molecules. Lipkowitz et al 10 studied the enantioselective binding of tryptophan with cyclodextrin using 1 H, 13 C NMR and molecular dynamic simulations.…”

Enantioselective chromatography of alkyl derivatives of 5‐ethyl‐5‐phenyl‐2‐thiobarbituric acid studied by semiempirical AM1 method

“…The phenyl ring pushes out all water molecules in the ␤-CD cavity, as was clearly shown for methylphenobarbitone. 8 Because of that, no water molecules are taken into account in our calculations. The differences in interactions of diastereomeric complexes for particular ligands with the nonchiral environment ought to be negligible.…”

“…6 The model is inspired by molecular mechanics research on the chiral chromatography of methylphenobarbitone 8 and other compounds. 9 Because of the size of ␤-cyclodextrin, for calculations of its guest-host complexes molecular mechanics methods [10][11][12][13] or semiempirical quantum-chemical calculations 14,15 are taken into consideration.…”