Diversity-based design, screening

Diversity-based Design of General Screening Libraries... 

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. 

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. 

The compound selection methods described thus far can be used to select compounds for screening from an in-house collection, or to select which compounds to purchase from an external supplier. In combinatorial library design, however, it is necessary to select subsets of reactants for actual synthesis. The two main strategies for combinatorial library design are reactant-based selection and product-based selection. In reactant-based selection, optimized subsets of reactants are selected without consideration of the products that will result and any of the compound selection methods already identified can be used. An early example of reactant-based design is that already described by Martin and colleagues which is based on experimental design and where diverse subsets of reactants were selected for the synthesis of peptoid libraries [1]. 

The next issue in the drug discovery process following definition of target and sources of diversity is the definition of a lead structure. Lead structures can arise from biochemical or cell-based screens or through structure-based design. Broach and Thorner provide a more exhaustive description of screening strategies than is possible here (14). 

Tlie complementarity of diversity and focussed approaches can be seen in clinical practice. HIV protease inliibitors are all from the rational, stractuie-based design school of dmg discovery, whereas the non-nucleoside HIV reverse transcriptase inhibitors have almost all originated from diversity screening. As combination therapy is the best way to treat HIV infection, tliis is evidence of the benefits of complementai y technologies to fight disease. 

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