Composition and applications of focus libraries to phenotypic assays.

Anne Mai Wassermann,Douglas S Auld,Luiz M Camargo

doi:10.3389/fphar.2014.00164

Abstract

The wealth of bioactivity information now available on low-molecular weight compounds has enabled a paradigm shift in chemical biology and early phase drug discovery efforts. Traditionally chemical libraries have been most commonly employed in screening approaches where a bioassay is used to characterize a chemical library in a random search for active samples. However, robust curating of bioassay data, establishment of ontologies enabling mining of large chemical biology datasets, and a wealth of public chemical biology information has made possible the establishment of highly annotated compound collections. Such annotated chemical libraries can now be used to build a pathway/target hypothesis and have led to a new view where chemical libraries are used to characterize a bioassay. In this article we discuss the types of compounds in these annotated libraries composed of tools, probes, and drugs. As well, we provide rationale and a few examples for how such libraries can enable phenotypic/forward chemical genomic approaches. As with any approach, there are several pitfalls that need to be considered and we also outline some strategies to avoid these.

Highlights

Chemical libraries employed for drug discovery ideally contain biologically active chemical scaffolds which are synthetically tractable
Through examining route of administration data pertaining to known drugs available from the World Drug Index (WDI), the physicochemical characteristics of well-absorbed drugs were defined based on four parameters: molecular weight (MW), lipophilicity, hydrogen bond donors, and hydrogen bond acceptors
Large archives containing analogs for known target classes, combinatorial collections, purified natural products, and diversity oriented synthesis usually employed in large scale high-throughput screening (HTS)-campaigns can be optimized by selecting a subset of compounds that maximize both biological and chemical diversity

Summary

Introduction

Chemical libraries employed for drug discovery ideally contain biologically active chemical scaffolds which are synthetically tractable. Chemical probes as applied to in vitro assay systems may have a more limited application compared to tool compounds as these are designed to modulate an isolated target protein or signaling pathway.

Results

Conclusion