Modeling in Chiral Chromatography

Keinan et al. found that the quantitative degree of chirality of substrates correlates with their efficiency of reaction with active sites [7]. The degree of chirality, a global shape descriptor, was determined by the use of the continuous chirality measure (CCM) methodology developed previously, which treats chirahty as a continuous structural property and not as a binary quality (chiral/not chiral) [8]. 

The generality of this new type of shape-activity correlation is demonstrated for five receptor/substrate systems trypsin/arylammonium inhibitors the D2-dop-amine receptor/dopamine derivative agonists trypsin/organophosphate inhibitors acetylcholinesterase/organophosphates and butyrylcholinesterase/organo-phosphates. The correlations were obtained both for active-site induced chiral conformers and for inherently chiral inhibitors. Interestingly, for some of these cases the correlation of activity with structure is hidden when classical parameters, such as chain length, are taken, but is revealed with this shape descriptor. 

The computational simulation of the interaction between analytes in a reversed 

multivariate analysis methods such as principle component analysis (PCA) and nonlinear mapping (NML), or comparative molecular field analysis (CoMFA) approaches and linear free energy-related (LFER) equations have been used to derive structure-retention relationships in chiral chromatography [16-18]. 

The group of Lipkowitz et al. also performed computational studies of chiral catalysts using COMFA of an asymmetric Diels-Alder reaction with catalysts containing bisoxazoline or phospinooxazoline ligands that are known to induce asymmetry [20]. Approximately 70% of the variance in the observed enantiomeric excess can be attributed to the sterical field and the remainder of the variance to the electrostatic field. 

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