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Ab initio and semi-empirical calculations were performed on the monomers, dimers and tetramers of the antidiabetic drug nateglinide to understand the conformational preferences and to explore their possible relation with polymorphism. The reported crystal structure of bis(nateglinide) hydronium chloride shows one asymmetric unit consisting of four different conformations of the drug nateglinide. The Becke, three-parameter, Lee–Yang–Parr /6-31+G(d,p) optimizations indicate that these conformers are energetically quite comparable and the differences disappear in gas phase. Our analysis shows that Φ (phi) torsion angle of this phenylalanine derivative is responsible for the observed differences in stability among the nateglinide conformations. Four different polymorphs of nateglinide (B, H, S and X2) were reported but the structural differences are not available. This quantum chemical study on the dimers of nateglinide helps in proposing the structures of polymorphs. As per the quantum chemical analysis, the dimer N-44 is the structure of the stable polymorph, whereas, the dimers N-AA, N-CC and N-AC are almost isoenergetic, thus proposed to be the structures of metastable state. The dimerization and tetramerization energies are estimated to be about � 9.0 and � 38.67kcal/mol, respectively. The extra stability in tetrameric state compared with the dimeric form is attributed to additional hydrophobic and van der Waals interactions. Copyright © 2011 John Wiley & Sons, Ltd. Supporting information may be found in the online version of this paper. |
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