Diversity-based design

Diversity-based Design of General Screening Libraries... 

Ideally, any diversity-based design using a similarity radius-based concept should result in a diverse, but representative child library. Not too few compounds should be selected to maintain information from the entire virtual library. Database self-similarity and comparison plots are useful tools in this context for analysis to monitor diversity, repre-sentivity and complementarity to a corporate collection, as shown schematically in Figure 13.11. 

The data on the epidemiology of anaphylaxis are widely varying estimates on the frequency of this condition. The findings are based on diverse study designs and are often not comparable. A clear conclusion from the data published so far is difficult. One major reason is that there is no universal consensus regarding the definition of anaphylaxis. The International Classification Codes (ICD) recording anaphylaxis are imprecise and do not properly reflect the epidemiological needs. 

Historically, ligand structure-based design has been the most widely used approach to the design of target-directed chemical libraries. Methods that start from hits or leads are among the most diverse, ranging from 2D substructure search and similarity-based techniques to analysis of 3D pharmacophores and molecular interaction fields (Fig. 15.2). 

Wyss PC, Gerber P, Hartman PG, Hubschwerlen C, Locher H, Marty HP, Stahl M. Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003 46 2304-12. 

S. U. Pillai, B. Himed, K. Y. Li, Waveform Diversity for Space Based Radar, Proc. of Waveform Diversity and Design, Edinburgh, Scotland, Nov 8-10, 2004. 

Key Words Biological activity cell-based partitioning chemical descriptors classification clustering distance-based design diversity selection high-throughput screening quantitative structure-activity relationship. 

In our study we compare two diversity-driven design methods (uniform cell coverage and clustering), two analysis methods motivated by similarity (cell-based analysis and cluster-classification), and two descriptor sets (BCUT and constitutional). Thus, our study addresses some of the many questions arising in a sequential screen how to choose the initial screen, how to analyze the structure-activity data, and what molecular descriptor set to use. The study is limited to one assay and thus cannot be definitive, but it at least provides preliminary insights and reveals some trends. 

Library design methods can be divided into reactant-based or product-based design. In reactant-based design, reactants are chosen without consideration of the products that will result. For example, diverse subsets of reactants are selected in the hope they will give rise to a diverse library of products. In product-based design, the selection of reactants is determined by analyzing the products that will be produced. 

Overall, the kinins are an important part of a well-organized physiological system. The various aspects and interdependencies of the kinin system have been, and continue to be, the focus of intensive research efforts in many laboratories. Many pharmaceutical companies have identified this system as an ideal site for therapeutic intervention in many inflammatory diseases. Hence, there have been many diverse approaches taken toward the discovery of antagonists (peptide and nonpeptide) of B2 and B1 receptors. This review focuses on the structure-based design strategies pursued in our laboratories during the past several years. 

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