Composition and applications of focus libraries to phenotypic assays

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.

Cheminformatics tools for analyzing and designing optimized small molecule libraries

“…Many focused libraries concentrate on a single druggable multigene family, such as kinases or ion-channels, FDA-approved drugs or the liganded genome 14 (the subset of proteins bound by at least three compounds at Ki < 10 µM); libraries against the liganded genome are commonly referred to as "Mechanism of Action" (MoA) libraries because they can be helpful in dissecting biological mechanism 15 . Such libraries have become available through public initiatives 16 , outreach by pharmaceutical companies 17 , commercial small molecule vendors and expert-curated lists of "optimal" compounds [18][19][20] , (e.g.…”

Cytotoxic Profiling of Annotated and Diverse Chemical Libraries Using Quantitative High-Throughput Screening

“…A second significant discovery screening strategy involves the creation of libraries of ‘annotated’ small molecules. Annotated libraries contain drugs, probes and tool molecules with one or more known mechanisms of action (4). They have emerged as information-rich databases to integrate both biological and chemical data.…”

Sterically Constrained and Encumbered: An Approach to the Naturally Occurring Peptidomimetic Tetrahydropyrazino[1,2‐a]indole‐1,4‐dione Core

“…[1] The term gained popularity in this century's era of chemical biology. [4] Among the dozens of privileged structures known to date, [5] the following two attracted our attention: indolines (1), which are present in a variety of bioactive small molecules (as summarized by Welsch [6] ), and 2,5-diketopiperazines (2), which are omnipresent in natural products [7] and have a special significance as a scaffold in medicinal chemistry. [4] Among the dozens of privileged structures known to date, [5] the following two attracted our attention: indolines (1), which are present in a variety of bioactive small molecules (as summarized by Welsch [6] ), and 2,5-diketopiperazines (2), which are omnipresent in natural products [7] and have a special significance as a scaffold in medicinal chemistry.…”