High-throughput drug discovery: What can we expect from HTS?

Gribbon, Philip; Sewing, Andreas

doi:10.1016/s1359-6446(04)03275-1

Cited by 163 publications

(72 citation statements)

References 37 publications

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“…Advances in robotic instrumentation, assay technologies, and compound libraries have greatly improved the feasibility, flexibility, and throughput of HTS (36,37). However, traditional HTS, performed at a single-compound concentration, remains relatively inefficient because of false-negative and -positive rates of up to 70% (29,38). This necessitates time-consuming selection and retesting of individual compounds to confirm their activity and characterize their pharmacology.…”

Section: Discussionmentioning

confidence: 99%

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Zheng

Padia

Urban

et al. 2007

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

137

130

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Gaucher disease is an autosomal recessive lysosomal storage disorder caused by mutations in the glucocerebrosidase gene. Missense mutations result in reduced enzyme activity that may be due to misfolding, raising the possibility of small-molecule chaperone correction of the defect. Screening large compound libraries by quantitative high-throughput screening (qHTS) provides comprehensive information on the potency, efficacy, and structureactivity relationships (SAR) of active compounds directly from the primary screen, facilitating identification of leads for medicinal chemistry optimization. We used qHTS to rapidly identify three structural series of potent, selective, nonsugar glucocerebrosidase inhibitors. The three structural classes had excellent potencies and efficacies and, importantly, high selectivity against closely related hydrolases. Preliminary SAR data were used to select compounds with high activity in both enzyme and cell-based assays. Compounds from two of these structural series increased N370S mutant glucocerebrosidase activity by 40 -90% in patient cell lines and enhanced lysosomal colocalization, indicating chaperone activity. These small molecules have potential as leads for chaperone therapy for Gaucher disease, and this paradigm promises to accelerate the development of leads for other rare genetic disorders.probe identification ͉ structure-activity relationship ͉ small-molecule inhibitor ͉ chaperone therapy

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Section: Discussionmentioning

confidence: 99%

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Zheng

Padia

Urban

et al. 2007

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

137

130

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“…High-throughput screening (HTS) is often the most efficient first step for identifying leads regarding new ligands or drugs in large libraries of chemical compounds (Gribbon and Sewing, 2005). Traditional HTS methods use automated plate readers for the measurement of absorbance, fluorescence intensity, fluorescence polarization, or luminescence.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Regulators of Receptor Internalization with High-Throughput Flow Cytometry

Tapia²,

Fisher³

et al. 2012

Mol Pharmacol

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We developed a platform combining fluorogen-activating protein (FAP) technology with high-throughput flow cytometry to detect real-time protein trafficking to and from the plasma membrane in living cells. The hybrid platform facilitates drug discovery for trafficking receptors such as G protein-coupled receptors and was validated with the ␤ 2 -adrenergic receptor (␤ 2 AR) system. When a chemical library containing ϳ1200 offpatent drugs was screened against cells expressing FAPtagged ␤ 2 ARs, all 33 known ␤ 2 AR-active ligands in the library were successfully identified, together with a number of compounds that might regulate receptor internalization in a nontraditional manner. Results indicated that the platform identified ligands of target proteins regardless of the associated signaling pathway; therefore, this approach presents opportunities to search for biased receptor modulators and is suitable for screening of multiplexed targets for improved efficiency. The results revealed that ligands may be biased with respect to the rate or duration of receptor internalization and that receptor internalization may be independent of activation of the mitogen-activated protein kinase pathway.

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“…The Clean Energy Project stands out from other computational materials science approaches as it combines conventional modeling with strategies from modern drug discovery [54][55][56][57][58][59][60][61]: CEP features an automated, highthroughput infrastructure for a systematic screening of millions of OPV candidates at a first-principles electronic structure level [62]. It also adopts techniques from cheminformatics [63,64] and heavily relies on data mining [65,66].…”

Section: The Harvard Clean Energy Projectmentioning

confidence: 99%

The Harvard Clean Energy Project: Large-Scale Computational Screening and Design of Organic Photovoltaics on the World Community Grid

Hachmann

Olivares‐Amaya

Atahan-Evrenk

et al. 2011

J. Phys. Chem. Lett.

589

565

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This perspective article introduces the Harvard Clean Energy Project (CEP), a theory-driven search for the next generation of organic solar cell materials. We give a broad overview of its setup and infrastructure, present first results, and outline upcoming developments.CEP has established an automated, high-throughput, in silico framework to study potential candidate structures for organic photovoltaics. The current project phase is concerned with the characterization of millions of molecular motifs using first-principles quantum chemistry. The scale of this study requires a correspondingly large computational resource which is provided by distributed volunteer computing on IBM's World Community Grid. The results are compiled and analyzed in a reference database and will be made available for public use. In addition to finding specific candidates with certain properties, it is the goal of CEP to illuminate and understand the structure-property relations in the domain of organic electronics. Such insights can open the door to a rational and systematic design of future high-performance materials. The computational work in CEP is tightly embedded in a collaboration with experimentalists, who provide valuable input and feedback to the project.

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High-throughput drug discovery: What can we expect from HTS?

Cited by 163 publications

References 37 publications

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease

Discovery of Regulators of Receptor Internalization with High-Throughput Flow Cytometry

The Harvard Clean Energy Project: Large-Scale Computational Screening and Design of Organic Photovoltaics on the World Community Grid

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