Filtering Computational Library Design

In general, the described techniques provide an effective, flexible, and relatively fast solution for library design based on analysis of bioscreening data. The quantitative relationships, based on the assessment of contribution values of various molecular descriptors, not only permit the estimation of potential biological activity of candidate compounds before synthesis but also provide information concerning the modification of the structural features necessary for this activity. Usually these techniques are applied in the form of computational filters for constraining the size of virtual combinatorial libraries and... 

Key words Fragment-based lead discovery, screening collection, library design, computational filtering, NMR screening... 

Chemical library design has always been an important component of chemoinformatics studies and it could be viewed in fact a special case of virtual screening. Chapter 9 by W. Zheng and S.R. Johnson provides an expert overview of computational approaches that are employed in the design of targeted and diverse chemical libraries, including the use of property i.e., ADMET) filters. 

The chapter begins with a discussion of similarity and diversity measures and how they can be applied in a virtual screening context. The various computational filters in use are also discussed. The rest of the chapter is concerned with different approaches to combinatorial library design, beginning with reagent-based methods followed by product-based approaches of cherry picking and combinatorial subset selection. Finally, approaches to designing libraries optimized on multiple properties simultaneously are discussed. 

To date, many of the reported ADME/Tox models have been rule based. For example, some research groups have used relatively simple filters like the rule of 5 [93] and others [94] to limit the types of molecules evaluated with in silico methods and to focus libraries for HTS. However, being designed as rapid computational alert tools aimed at a single property of interest, they cannot offer a comprehensive picture when it comes to understanding ADME properties. 

Charifson PS, Walters WP. (2002) Filtering databases and chemical libraries. /. Comput.-Aid. Mol. Design 16 311-323. 

Control the size of the enumerated library As the name implies, combinatorial libraries can explode in size very quickly. Therefore one must perform reactant-level selections before product enumeration in most design cases. As shown in the example library, molecular weight (MW) is an effective filter to cut down number of reactants, so is reactant availability inside the reactant inventory system. As a matter of principle, more expensive computational approaches (e.g., protein-ligand docking and scoring) should be applied only to smaller subsets of reactants or products. 

Chemical libraries are the topic of the final section and cover chemogenomics in compound library and template design for GPCRs (T. R. Webb), computational filters in lead generation (W. Guba), navigation in chemical space (G. Schneider... 

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