Virtual screening molecular similarity analysis

Godden JW, Furr JR, Xue L et al. (2004) Molecular similarity analysis and virtual screening by mapping of consensus positions in binary-transformed chemical descriptor spaces with variable dimensionality. J Chem Inf Comput Sci 44 21-29. 

Eckert, H. and Bajorath, J. 2007. Molecular similarity analysis in virtual screening foundations, limitations and novel approaches. Drug Disc. Today 12, 225-233. 

Implications for Molecular Similarity Analysis and Virtual Screening... 

In this chapter we have discussed the foundations of molecular similarity analysis that are largely responsible for success or failure of similarity-based methods in the context of virtual compound screening. Furthermore, we have described how crucial underlying SAR characteristics are for molecular similarity analysis and presented a comprehensive methodological framework for the qualitative and quantitative analysis of SARs and the classification of different SAR types. 

Peltason, L. and Bajorath, J. (2007). Molecular similarity analysis uncovers heterogeneous structure-activity relationships and variable activity landscapes. Chem. Biol. 14, 489 97. Peltason, L. and Bajorath, J. (2008). Molecular similarity analysis in virtual screening. In "Chemoinformatics Approaches to Virtual Screening", (A. Vamek and A. Tropsha, eds), pp. 120-147. RSC Publishing, Cambridge, UK. 

Eckert, H., Vogt, I. and Bajorath, J. (2006) Mapping algorithms for molecular similarity analysis and ligand-based virtual screening design of DynaMAD and comparison with MAD and DMC. /. Chem. Inf. Model, 46, 1623-1634. 

The concepts of molecular similarity (1-3) and molecular diversity (4,5) play important roles in modern approaches to computer-aided molecular design. Molecular similarity provides the simplest, and most widely used, method for virtual screening and underlies the use of clustering methods on chemical databases. Molecular diversity analysis provides a range of tools for exploring the extent to which a set of molecules spans structural space, and underlies many approaches to compound selection and to the design of combinatorial libraries. Many different similarity and diversity methods have been described in the literature, and new methods continue to appear. This raises the question of how one can compare different methods, so as to identify the most appropriate method(s) for some particular application this chapter provides an overview of the ways in which this can be carried out, illustrating such comparisons by,... 

The conceptual basis for similarity analysis is provided by the similarity-property principle that states that similar molecules have similar biological activity.This rather intuitive principle has been widely accepted and substantiated by a wealth of observations. The success of many similarity-based virtual screening calculations can only be rationalized on the basis of this principle. However, minor modifications in molecular structure can dramatically alter the biological activity of a small molecule. This situation is exploited in lead optimization elforts, but limits the potential of similarity methods. These considerations also suggest that there must be fundamental dilferences between the structure-activity relationships (SARs). Thus, difierent types of SARs are expected to critically determine the success of similarity methods and systematic SAR analysis helps to better understand on a case-by-case basis why similarity methods might succeed or fail. 

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