Novel Statistical Approach for Primary High-Throughput Screening Hit Selection

Yan, S. Frank; Asatryan, Hayk; Li, Jing; Zhou, Yingyao

doi:10.1021/ci0502808

Cited by 35 publications

(44 citation statements)

References 44 publications

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“…Chemical scaffold analysis based on chemical fingerprint similarities (13) revealed that the library of 5697 compounds comprised of 2715 independent chemical scaffold clusters, some of which were unique to this library and some of which were also hits in independent screens (Fig. S2).…”

Section: A Majority Of Compounds Active Against Blood Stages Is Inactmentioning

confidence: 99%

“…Such filtering still gives more leads than can be reasonably investigated, but the advantage of completing such a large screen of putative antimalarials is that it allows for a system-wide analysis of the data by exploring structure-activity relationships (SAR) within the compound library. SARs are more important than absolute potency because they indicate a chemical space that can be optimized to compounds with the desired potency (13). …”

Section: Scaffold Clusteringmentioning

confidence: 99%

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Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery

Meister

Plouffe

Kuhen

et al. 2011

Science

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326

367

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Most malaria drug development focuses on parasite stages detected in red-blood cells even though to achieve eradication next-generation drugs active against both erythrocytic and exo-erythrocytic forms would be preferable. We applied a multifactorial approach to a set of >4,000 commercially available compounds with previously demonstrated blood stage activity (IC50 < 1 μM), and identified chemical scaffolds with potent activity against both forms. From this screen, we identified an imidazolopiperazine scaffold series that was highly enriched among compounds active against Plasmodium liver stages. Our orally bioavailable lead imidazolopiperazine confers complete causal prophylactic protection (15 mg/kg) in rodent models of malaria and shows potent in vivo blood-stage therapeutic activity. The open source chemical tools resulting from our effort provide starting points for future drug discovery programs, as well as opportunities for researchers to investigate the biology of exo-erythrocytic forms.

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Section: A Majority Of Compounds Active Against Blood Stages Is Inactmentioning

confidence: 99%

Section: Scaffold Clusteringmentioning

confidence: 99%

Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery

Meister

Plouffe

Kuhen

et al. 2011

Science

Self Cite

326

367

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show abstract

“…To assess the utility of the screen in terms of novel structural motifs, confirmed HTS hits were first clustered based on the chemical similarity (20), resulting in the identification of Ϸ530 different classes (cluster size Ն3) with a similarity metric of 0.85 or higher. The distribution of different scaffolds is shown in Fig.…”

Section: ϫ10mentioning

confidence: 99%

In silico activity profiling reveals the mechanism of action of antimalarials discovered in a high-throughput screen

Plouffe

Brinker

McNamara

et al. 2008

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

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The growing resistance to current first-line antimalarial drugs represents a major health challenge. To facilitate the discovery of new antimalarials, we have implemented an efficient and robust highthroughput cell-based screen (1,536-well format) based on proliferation of Plasmodium falciparum (Pf) in erythrocytes. From a screen of Ϸ1.7 million compounds, we identified a diverse collection of Ϸ6,000 small molecules comprised of >530 distinct scaffolds, all of which show potent antimalarial activity (<1.25 M). Most known antimalarials were identified in this screen, thus validating our approach. In addition, we identified many novel chemical scaffolds, which likely act through both known and novel pathways. We further show that in some cases the mechanism of action of these antimalarials can be determined by in silico compound activity profiling. This method uses large datasets from unrelated cellular and biochemical screens and the guilt-by-association principle to predict which cellular pathway and/or protein target is being inhibited by select compounds. In addition, the screening method has the potential to provide the malaria community with many new starting points for the development of biological probes and drugs with novel antiparasitic activities.antifolates ͉ cheminformatics ͉ high-throughput screening ͉ Plasmodium falciparum

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“…If gene set can be defined reliably from prior biological knowledge, GSEA can be powerful in enhancing the signal-to-noise ratio and make it possible to detect modest changes in individual genes that would be hard to detect in single gene analysis. Yan et al (2005) and Zhou et al (2005) have also proposed similar approaches, called ontology-based pattern identification (OPI) score, to improve screening results by incorporating both the activity ranking and the number of structurally/functionally related genes. A deterministic threshold widely used and preferred by many biologists is fold change (FC).…”

Section: Target Discoverymentioning

confidence: 99%