Bioisosteric descriptors

D.E., and Ferguson, A.M. Bioisosterism as a molecular diversity descriptor steric fields of single topomeric conformers. 12... 

One might fear that the traditional descriptors are whole molecule properties that cannot distinguish the details of important substructural differences. It is difficult to quantify the wholism of a descriptor. A qualitative definition might be that a whole molecule property is one in which small bioisosteric... 

CATS3D was not only successful in scaffold hopping on the basis of the definition above (Meqi). We also observed a substructure hopping , which might be seen as an equivalent to more traditional bioisosteric replacement strategies. It seems that the CATS descriptor family represents molecules in a way that allows a combination of scaffold hopping and substructure hopping at once. This can result in a selection of molecules which would not be considered similar by other methods such as the MACCS keys. 

Sets of substituent pairs of 418 bioisosteric fragments from Bioster 98.1 were used for the validation of the newly defined R-group descriptors, characterizing the physicochemical properties of ring substituents, to (dis)similarity estimation [58]. 

In order to calculate the similarity between fragments (substituents, spacers, or rings) that one wants to replace in the process of bioisosteric design, it is necessary to quantify somehow their properties and express them as a set of numerical values -descriptors. In the classical years of quantitative structure-activity relationship (QSAR), the properties of substituents were mostly characterized by experimentally derived parameters. Hammett sigma constants a (and several variations of this parameter) played a prominent role in characterizing the electron-donating or electron-accepting power of substituents 7], and the Hansch n parameter, defined... 

The molecular representations and descriptors chscussed here provide a brief overview of the methods apphed in chemical information systems and their conventions. Many of the terms defined here will be of use in understanding the remainder of this chapter on using molecular topology (or graph) representations in identifying bioisosteres. 

However, perhaps a more rational approach is to characterize mined fragments using computational parameters that have been correlated with being able to identify bioisosteres [19], which was covered in Chapter 7. An alternative approach to using these types of mined fragments is from Holliday et al. [20] using R-group descriptors (see below). 

The work from Wagener and Lommerse [26] detailed a new ligand-based topological pharmacophore descriptor specifically for the identification of bioisosteres and can be seen as an approach to alleviate the issues of sensitivity to heteroatom replacement observed by Schuffenhauer et al. The descriptors applied in this work used an atom pair representation similar to that reported by Carhart et al. [28]. These descriptors are extracted from databases of known molecules by shredding the molecules at all deavable bonds with the attachment point being retained as a distinct atom type, X. 

Of the eight descriptors used in this analysis, the molecular weight and molar refractivity were demonstrated to be the most significant in improving the separation of experimentally observed bioisosteres from the nonbioisosteric data set. However, molecular weight and refractivity are highly correlated, so only one of these properties may be necessary to assist in the discrimination of these two data sets. 

One can describe a molecule in many ways and the same applies to bioisosteres. Molecular descriptor methods are covered in the third part by the application of different representations. A number of computational approaches to bioisosteric replacement are covered in chapters on physicochemical properties, molecular topology, molecular shape, and the use of protein structure information. Each chapter covers many common methods and overviews of when best to apply these methods, and where they have been successfully applied. 

R. D. Cramer, R. D. Clark, D. E. Patterson, and A. M. Fergusson,/. Med. Chem., 39, 3060 (1996). Bioisosterism as a Molecular Diversity Descriptor Stcric Fields of Single Topo-ineric Conformers. 

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