Molecular diversity analysis

R.A. Lewis, S.D. Pickett, D.E. Qark. Computer-aided molecular diversity analysis and combinatorial library design, in Reviews in Computational Chemistry, Vol. 16, K.B. Opkowitz, D.B. Boyd (Eds.). Wiley-VCH, New York. 2000. pp. 8-51. 

Richard A. Lewis, Stephen D. Pickett, and David E. Clark, Computer-Aided Molecular Diversity Analysis and Combinatorial Library Design. 

D.E. Computer-aided molecular diversity analysis and combinatorial library design. Rev. Comput. Chem. 2000, 14... 

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 principal aim of molecular diversity analysis is to identify structurally diverse (synonyms are dissimilar, disparate, and heterogeneous) sets of compounds that can then be tested for bioactivity, the assumption being that a structurally diverse set will generate more structure-activity information than will a set of compounds identified at random. The sets of compounds can be selected from an existing corporate or public database, or can be the result of a systematic combinatorial library design process (4,5). 

Blaney, J., Martin, E. (1997) Computational approaches for combinatorial library design and molecular diversity analysis. Curr Opin Chem Biol 1, 54-59. 

Molecular diversity analysis is useful in several contexts ... 

Wikel, J. H. and Higgs, R. E. (1997). Point Applications of molecular diversity analysis in high throughput screening. Journal of Biomolecular Screening, 2, 65-66. 

Weber L (2000) Molecular diversity analysis and combinatorial library design In Clark DE (ed) Evolutionary algorithms in molecular design. Wiley-VCH, Weinheim... 

This chapter is concerned with some of the background theory for molecular diversity analysis and includes a discussion of diversity indices, intermolecular similarity and dissimilarity measures. The extent to which the different approaches to diversity analysis have been validated and compared is reviewed. Algorithms for the selection of diverse sets of compounds are covered in detail elsewhere in this book and are mentioned only briefly here. However, consideration is given to whether these algorithms should be applied in reactant or product space. 

Blaney, J.M. and Martin, E.J. Computational Approaches for Combinatorial Library Design and Molecular Diversity Analysis. Curr. Opin. Chem. Biol.. 1997, 1,54-59. 

The first application using MDS in molecular diversity analysis was introduced by a group at Chiron as a means of reducing the enormous dimensionality of binary chemical descriptors They found that 2048-bit Daylight fingerprints associated with 721 commercially available primary amines could be reduced to only five dimensions that reproduced all 260,000 original dissimilarities with a standard deviation of only 10%. Similarly, only seven dimensions were required to reduce the 642,000 pairwise similarities among a set of 1133 carboxylic acids and acid chlorides to the same standard deviation. 

Computer-Aided Molecular Diversity Analysis and Combinatorial Library Design. 

Molecular Diversity Analysis descriptor = MolDiA descriptor —> substructure descriptors (0... 

MolDiA descriptors Molecular Diversity Analysis descriptors) are string representations encoding information about cyclic and acyclic fragments present in the molecules [Maldonado, Doucet et al, 2007]. These fragments are identified by breaking down each molecule into its constituent independent cycles and atomic units defined by their specific environment and matching them with fragments of a predefined dictionary. 

Maldonado, A.G., Doucet, J.P., Petitjean, M. and Fan, B.T. (2007) MolDlA a novel molecular diversity analysis tool. 1. Principles and architecture. 

In this chapter, we will start by providing an overview of the evolution of the 3D pharmacophore concept and subsequently show the usefulness of 3D pharmacophore searching in modern lead discovery. The use of this approach for combinatorial library design, compound classification, and molecular diversity analysis is presented. Examples of successful applications reported in the last couple of years are reviewed. 

Molecular similarity The degree of similarity between molecules, although quantitatively measurable, very much depends on what molecular features are used to establish the degree of similarity. One of the many comparators is the electron density of a pair of molecules. Other comparators include electrostatic potentials, reactivity indices, hydrophobicity potentials, molecular geometry such as distances and angles between key atoms, solvent accessible surface area, etc. It is an open question as to how much or what part(s) of the molecular structure is to be compared. The Tanimoto coefficient which compares dissimilarity to similarity is often used in molecular diversity analysis. 

Approaches for Combinatorial Library Design and Molecular Diversity Analysis. 

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