Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Ziegler, Slava; Pries, Verena; Hedberg, Christian; Waldmann, Herbert

doi:10.1002/anie.201208749

Cited by 414 publications

(378 citation statements)

References 285 publications

(306 reference statements)

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“…Identifying the targets of small molecules is a major obstacle in biomedical research (23)(24)(25). Phenotypic high-throughput screens using small-molecule libraries often result in the identification of numerous molecules with unknown targets.…”

Section: Discussionmentioning

confidence: 99%

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

Surdel

Horvath

Lojek

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Gram-positive bacteria cause the majority of skin and soft tissue infections (SSTIs), resulting in the most common reason for clinic visits in the United States. Recently, it was discovered that Gram-positive pathogens use a unique heme biosynthesis pathway, which implicates this pathway as a target for development of antibacterial therapies. We report here the identification of a small-molecule activator of coproporphyrinogen oxidase (CgoX) from Gram-positive bacteria, an enzyme essential for heme biosynthesis. Activation of CgoX induces accumulation of coproporphyrin III and leads to photosensitization of Gram-positive pathogens. In combination with light, CgoX activation reduces bacterial burden in murine models of SSTI. Thus, small-molecule activation of CgoX represents an effective strategy for the development of light-based antimicrobial therapies.

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Section: Discussionmentioning

confidence: 99%

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

Surdel

Horvath

Lojek

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Whole animal testing via cassette dosing is a procedure adapted by HTS to rapidly access pharmacokinetics of many drugs. Drug affinity responsive target stability (DARTS) and Target Identification by Chromatographic Co-Elution (TICC) methods can make target identification easier [12,13]. Dropletbased micro fluidic approaches involve working with reduced sample volumes and single-cell analysis capabilities.…”

Section: Futurementioning

confidence: 99%

High Throughput Screening of Small Molecule Library: Procedure, Challenges and Future

Shukla¹

2016

JCPCR

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High-throughput screening (HTS) of small molecules is used to identify and characterize chemical compounds based on their response on particular assays. The screened compounds can be further used as tools to study complex molecular pathways involved in progression of cancers and potential candidates can be further developed as drugs. Testing of vast number of compounds and fast readout technologies for assays in a timely manner has made this procedure a popular drug-discovery process, which is widely used in the pharmaceutical industry. However, the procedure of screening is a multi-step process and is prone to give false positive and false negative results. Assurance of quality and good analysis of results play critical role in finding a true product. Technological hardware like robotic plate handling is critical for the procedure. Reagents like antibodies and recombinant proteins can also make the whole procedure very expensive. Increased number of available compounds and molecular targets has raised the requirements for even faster procedures, more sensitive assays to run and even smaller sample size assays for screening. Development of new methods like Droplet-based cell encapsulation technology has given hope for a better future of HTS. Keywords: High-throughput screening (HTS); Small molecules; Target identification; Assay design IntroductionCancer kills around 7.6 million people worldwide every year and about a half million people in the US annually. Early detection and more effective chemotherapy have improved cure rate among patients. However, patients diagnosed with advanced stage cancers still have very few options for treatment. It has been shown that there are short and long term adverse effects of chemotherapy. Both adult and pediatric cancer survivors face significant health burdens including but not limited to impaired end-organ function, risk of secondary cancers and shortened life expectancies [1,2].Development of personalized medicine strategy is becoming more popular. It focuses on identifying drugs that can target a molecular pathway or more specifically a protein involved in an uncontrolled or disrupted signaling pathway leading to the progression of particular cancer. Genetics studies are confirming addictions and weaknesses of cancer cells on such pathways and specific molecules. With this approach, normal tissues are spared from getting targeted by toxic chemotherapies.Drug discovery programs start to find a cure for a disease, which does not have suitable treatment available. Data generated by primary research suggest involvement of specific proteins in the progression of diseases and can be used as target for drug development [3]. An assay is then developed that can be used to screen small molecule chemical libraries The whole process of HTS can be divided into steps of target identification, assay design, primary and secondary screens, data analysis and identification of hits (Figure 1). The role of HTS is not only limited to identifying new compounds but is also useful in ass...

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“…Identification of the targets from a phenotypic screen can often be the rate-limiting step 39 . However, careful observation of the phenotype may sometimes offer clues as to what the target may be, allowing more informed experiments to be conducted 40 .…”

Section: Library Synthesismentioning

confidence: 99%

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

et al. 2014

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The synthesis of diverse three-dimensional libraries has become of paramount importance for obtaining better leads for drug discovery. Such libraries are predicted to fare better than traditional compound collections in phenotypic screens and against difficult targets. Herein we report the diversity-oriented synthesis of a compound library using rhodium carbenoid chemistry to access structurally diverse three-dimensional molecules and show that they access biologically relevant areas of chemical space using cheminformatic analysis. Highcontent screening of this library for antimitotic activity followed by chemical modification identified 'Dosabulin', which causes mitotic arrest and cancer cell death by apoptosis. Its mechanism of action is determined to be microtubule depolymerization, and the compound is shown to not significantly affect vinblastine binding to tubulin; however, experiments suggest binding to a site vicinal or allosteric to Colchicine. This work validates the combination of diversity-oriented synthesis and phenotypic screening as a strategy for the discovery of biologically relevant chemical entities.

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Target Identification for Small Bioactive Molecules: Finding the Needle in the Haystack

Cited by 414 publications

References 285 publications

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

High Throughput Screening of Small Molecule Library: Procedure, Challenges and Future

Diversity-oriented synthesis as a tool for identifying new modulators of mitosis

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