Molecular similarity analysis

Molecular similarity analysis has developed substantially over the years, especially as digital computers became faster, more compact, and widely available to scientists. Handling large sets of molecules is generally not a problem. The main problem confronting MSA is the problem of the lack of topological invariance of the chemistry spaces induced by the various similarity measures. Unfortunately, this problem may be fundamentally related to the inherent subjectivity of similarity and thus cannot be addressed in any simple manner. 

Johnson, M. A. (1989) A review and examination of mathematical spaces underlying molecular similarity analysis. J. Math. Chem. 3, 117-145. 

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. 

The approach we shall follow in the study of host-guest interactions involves the comparison of electron density distributions of molecular regions in the presence and also in the absence of interactions. In this context, some aspects of molecular similarity analysis are applied, evaluating the similarities between two electron densities one where these regions are taken in isolation, and another that includes the interactions between the host and guest regions of the molecules involved. 

A theoretical foundation of molecular similarity analysis is the assumption of neighborhood behavior ,which refers to the tendency of molecules with globally similar structures to exhibit similar biological activity. The well-known similarity-property principle (SPP) of Johnson and Maggiora expresses this paradigm and promotes a holistic view of molecular structure and properties. Molecular similarity applications assume that chemical similarity can be related to biological activity in a meaningful manner. However, the success of this approach ultimately depends on the way molecular similarity is defined. 

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. 

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