Chirality descriptors

Molecular chirality is of profound importance in many areas of chemistry. The biological and chemical properties exhibited by opposite enantiomers of chiral compounds are frequently different. This subtle geometrical fact has profound practical consequences in biology, environmental sciences and pharmacology. Particularly, the fact that two enantiomers often have different biological activity makes chirality one of the most important factors in drug safety evaluation today. The chemical and pharmaceutical industries are being forced for safety reasons to commercialize single enantiomers (enantiopure compounds), and drug companies use chirality as a tool for drug life-cycle management, and to redevelop racemic mixtures as single enantiomers (racemic switch).

The development of enantiomerically pure drugs and agro-chemicals has become imperative which demands improved enantioselective methods in organic synthesis, analytical chemistry, separation techniques, and property prediction. Computer applications to predict chiral properties starting from the molecular structure require an adequate representation of molecular chirality.

Particularly in molecular diversity studies and quantitative structure-activity relationships (QSAR) that are influenced by chiral properties, molecular representations incorporating information about chirality are crucial.

Back in 1998, together with the Gasteiger group we've developed a chirality code that represents the chirality generated by chiral carbon atoms and is independent of conformation. This code is a molecular transform that represents chirality using a spectrum-like, fixed-length code, and includes information about the geometry of chiral centers, properties of the atoms in their neighborhoods, bond lengths, and distinguishes between enantiomers. Additionally, it was demonstrated that such a code can be successfully applied to the prediction of the enantiomeric selectivity in chemical reactions using artificial neural networks ( J. Aires-de-Sousa, J. Gasteiger, J. Chem. Inf. Comp. Sci., 2001,41 (2), 369-375 ). This code has the advantage of describing chirality without being influenced by the conformation. However, it is restricted to applications in which the chirality arises from a chiral carbon (or at least a chiral atom). For example it cannot be applied to axially chiral compounds in which a locked conformation generates chirality.

Later we proposed a second chirality code that characterizes the chirality of a 3D structure considered as a rigid set of points (atoms) with properties (atomic properties) and connected by bonds. The code includes information about the molecular geometry (including 3D interatomic distances), connectivity, atomic properties, and can distinguish between enantiomers. It depends on the conformation and has the form of radial distribution functions as used in X-ray structure determination. It was shown that the conformation-dependent chirality code (CDCC) can be correlated by means of Kohonen neural networks with the elution order of enantiomers in chiral chromatographic separations (J. Aires-de-Sousa, J. Gasteiger, J. Molec. Graphics and Model., 2002, 20(5), 373-388).

Chirality codes were applied to the automatic assignment of absolute configuration from 1D NMR data (Q.-Y. Zhang, G. Carrera, M. J. S. Gomes, J. Aires-de-Sousa, "Automatic assignment of absolute configuration from 1D NMR data", J. Org. Chem. 2005, 70(6), 2120-2130). Chirality codes were also used in the  representation of metabolic reactions catalysed by racemases and epimerases of E.C. subclass 5.1. (D. A. R. S. Latino, Q.-Y. Zhang, J. Aires-de-Sousa, "Genome-scale classification of metabolic reactions and assignment of EC numbers with self-organizing maps", Bioinformatics 2008, 24(19), 2236-2244).

Physicochemical atomic stereodescriptors (PAS) were proposed in 2006 to represent the chirality of an atomic chiral center on the basis of empirical physicochemical properties of its ligands – the ligands are ranked according to a specific property, and the chiral center takes an “S/R-like” descriptor relative to that property. The procedure is performed for a series of properties, yielding a chirality profile: Q.-Y. Zhang, J. Aires-de-Sousa, "Physicochemical Stereodescriptors of Atomic Chiral Centers", J. Chem. Inf. Model. 2006, 46(6), 2278-2287.