Design of Combinatorial Libraries

HTS data as well as virtual screening can guide and direct the design of combinatorial libraries. A genetic algorithm (GA) can be applied to the generation of combinatorial libraries [18. The number of compounds accessible by combinatorial synthesis often exceeds the number of compounds which can be syiithcsii ed 

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Drewry D H and S S Young 1999. Approaches to the Design of Combinatorial Libraries. Chemometrics in Intelligent Laboratory Systems 48 1-20. 

E J, J M Blaney, M A Siani, D C Spellmeyer, A K Wong and W H Moos 1995. Measuring fersity Experimental Design of Combinatorial Libraries for Drug Discovery. Journal of dicinal Chemistry 38 1431-1436. 

Experimental design of combinatorial libraries for drug discovery. J Med Chem 38(9) 1431-1436, 1995. 

Mason JS, Morize 1, Menard PR, Cheney DL, Hulme C, Labaudiniere RF. New 4-point pharmacophore method for molecular similarity and diversity applications Overview of the method and applications, including a novel approach to the design of combinatorial libraries containing privileged substructures. I Med Chem 1999 42 3251-64. 

Beno BR, Mason JS. The design of combinatorial libraries using properties and 3D pharmacophore fingerprints. Drug Discov Today 2001 6(5) 251-8. 

TABLE 15.1 Specialized Computational Technologies for Target Structure-Based Design of Combinatorial Libraries... 

Considerable interest is focused on the calculahon of H-bonding capability in the design of combinatorial libraries, for assessing the potenhal for oral absorphon and permeability [16, 62-65]. A number of different descriptors for H-bonding have been discussed [66], one of the simplest being the count of the number of H-bond forming atoms [67]. 

Closely related to the use of PSA in virtual screening is its application in the design of combinatorial libraries with optimal properties. These applications are reviewed further in Refs. [46, 47], for example. 

The next vague of tools will be around computational or in silico ADME approaches. These will allow to include ADME into the design of combinatorial libraries, the evaluation of virtual libraries, as well as in selecting the most promising compounds to go through a battery of in vitro screens, possibly even replacing some of these experimental screens. Several of these computational tools are currently under development as will be discussed in this volume. 

Spellmeyee, D.C., Wong, A.K., and Moos, W.H. Measuring diversity experimental design of combinatorial libraries for dmg discovery. J. Med. 

Lipinski, C.A. Integration of physicochemical property considerations into the design of combinatorial libraries. Pharm. Nears 2002, 9, 195-202. 

Mason JS, Morize I, Menard PR, Cheney DL, Huhne C, Labaudiniere RF. (1999) New 4-Point Pharmacophore Method for Molecular Similarity and Diversity Appheations Overview of the Method and Applications, including a Novel Approach to the Design of Combinatorial Libraries Containing Privileged Substructures. J. Med. Chem. 42 3251-3264. 

Bohl M, Dunbar JB, Gifford EM, Heritage T, Wild DJ, Willett P, Wilton DJ. (2002) Scaffold Searching Automated Identification of Similar Ring Systems for the Design of Combinatorial Libraries. Quant. Struct.-Act. Rel. 21 590-597. 

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,... 

Jamois, E. A., Hassan, M., and Waldman, M. (2000) Evaluation of reactant-based and product-based strategies in the design of combinatorial library subsets. 

Gillet, V. J. (2002) Reactant- and product-based approaches to the design of combinatorial libraries. J Comput Aided Mol Des 16 371-380. 

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