Recent Trends and Observations in the Design of High-Quality Screening Collections

Renner, Steffen; Popov, Maxim; Schuffenhauer, Ansgar; Roth, Hans-Joerg; Breitenstein, Werner; Marzinzik, Andreas L.; Lewis, Ian; Krastel, Philipp; Nigsch, Florian; Jenkins, Jeremy L.; Jacoby, Edgar

doi:10.4155/fmc.11.15

Cited by 62 publications

(69 citation statements)

References 169 publications

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“…Similarly, gene expression profiling of compounds can shed light on the processes regulated by the bioactive molecules. Computational approaches to establish polypharmacology of compounds have been developed employing either properties of the ligand or the structure of the targets (Houghten et al, 2006, 2008; Hopkins, 2008; Weill and Rognan, 2009; Renner et al, 2011). In addition, by combining gene expression and protein interaction networks, systems biology based methods are also employed to reverse engineer the upstream targets that best explain the gene expression profile (i.e., pleiotropic effects of a compound; Jaeger et al, 2014).…”

Section: Analysis and Interpretation Of Annotated Chemical Library Datamentioning

confidence: 99%

Composition and applications of focus libraries to phenotypic assays

Wassermann¹,

Camargo²,

Auld³

2014

Front. Pharmacol.

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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.

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Section: Analysis and Interpretation Of Annotated Chemical Library Datamentioning

confidence: 99%

Composition and applications of focus libraries to phenotypic assays

Wassermann¹,

Camargo²,

Auld³

2014

Front. Pharmacol.

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“…Similarly, chemical-protein hybrids (109), secondary structure mimetics (110), aptamers (111), and antibody-like molecules (112) have been developed in an attempt to better match the topology of PPIs. Finally, natural products, metabolites and natural product-like collections are finding renewed use as sources of PPI modulators (113, 114). Unfortunately, these concepts have still not been widely adapted by public screening facilities; as of 2010, only 1% of the NIH Molecular Libraries Small Molecule Repository was natural product-like (106).…”

Section: Towards Compound Libraries Enriched For Ppi Inhibitorsmentioning

confidence: 99%

Fine-Tuning Multiprotein Complexes Using Small Molecules

et al. 2012

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Multi-protein complexes such as the transcriptional machinery, signaling hubs, and protein folding machines are typically comprised of at least one enzyme combined with multiple non-enzymes. Often the components of these complexes are incorporated in a combinatorial manner, in which the ultimate composition of the system helps dictate the type, location, or duration of cellular activities. Although drugs and chemical probes have traditionally targeted the enzyme components, emerging strategies call for controlling the function of protein complexes by modulation of protein-protein interactions (PPI). However, the challenges of targeting PPIs have been well documented and the diversity of PPIs makes a “one-size-fits-all” solution highly unlikely. These hurdles are particularly daunting for PPIs that encompass large buried surface areas and those with weak affinities. In this review, we discuss lessons from natural systems, in which allostery and other mechanisms are used to overcome the challenge of regulating the most difficult PPIs. These systems may provide a blueprint for identifying small molecules that target challenging PPIs and affecting molecular decision-making within multi-protein systems.

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“…3−5 The combined corporate, academic, and commercial collections worldwide probably total over 100 million different small molecules. 6 Despite these impressive numbers, it has become increasingly difficult to develop new small molecule drugs, largely due to lack of efficacy, side effects, and toxicity issues. 7,8 De novo drug design 9−12 may help to address this problem by investigating even much larger numbers of yet unknown molecules by virtual screening 13−15 in search of innovative structures that might exhibit improved selectivity and ADMET profiles.…”

Section: ■ Introductionmentioning

confidence: 99%

Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

Ruddigkeit

Deursen

Blum

et al. 2012

J. Chem. Inf. Model.

1,218

1,088

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Drug molecules consist of a few tens of atoms connected by covalent bonds. How many such molecules are possible in total and what is their structure? This question is of pressing interest in medicinal chemistry to help solve the problems of drug potency, selectivity, and toxicity and reduce attrition rates by pointing to new molecular series. To better define the unknown chemical space, we have enumerated 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens forming the chemical universe database GDB-17, covering a size range containing many drugs and typical for lead compounds. GDB-17 contains millions of isomers of known drugs, including analogs with high shape similarity to the parent drug. Compared to known molecules in PubChem, GDB-17 molecules are much richer in nonaromatic heterocycles, quaternary centers, and stereoisomers, densely populate the third dimension in shape space, and represent many more scaffold types.

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Recent Trends and Observations in the Design of High-Quality Screening Collections

Cited by 62 publications

References 169 publications

Composition and applications of focus libraries to phenotypic assays

Composition and applications of focus libraries to phenotypic assays

Fine-Tuning Multiprotein Complexes Using Small Molecules

Enumeration of 166 Billion Organic Small Molecules in the Chemical Universe Database GDB-17

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