Jove
Visualize
Contact Us
JoVE
x logofacebook logolinkedin logoyoutube logo
ABOUT JoVE
OverviewLeadershipBlogJoVE Help Center
AUTHORS
Publishing ProcessEditorial BoardScope & PoliciesPeer ReviewFAQSubmit
LIBRARIANS
TestimonialsSubscriptionsAccessResourcesLibrary Advisory BoardFAQ
RESEARCH
JoVE JournalMethods CollectionsJoVE Encyclopedia of ExperimentsArchive
EDUCATION
JoVE CoreJoVE BusinessJoVE Science EducationJoVE Lab ManualFaculty Resource CenterFaculty Site
Terms & Conditions of Use
Privacy Policy
Policies

Related Experiment Videos

High-throughput assays for promiscuous inhibitors.

Brian Y Feng1, Anang Shelat, Thompson N Doman

  • 1Department of Pharmaceutical Chemistry & Graduate Group in Chemistry and Chemical Biology, 1700 4th St., University of California San Francisco, San Francisco, California 94143-2550, USA.

Nature Chemical Biology
|January 13, 2006
PubMed
Summary

Nonspecific inhibitors in drug discovery can form aggregates that inhibit enzymes. This study introduces rapid assays to detect these promiscuous aggregates, aiding in more reliable early-stage drug discovery.

Related Concept Videos

You might also read

Related Articles

Articles linked to this work by shared authors, journal, and citation graph.

Sort by
Same author

Modeling the Sensitivity of Large-Scale Virtual Screening to Scoring Function Accuracy, Artifacts, and Library Composition.

Journal of chemical information and modeling·2026
Same author

Library Docking for Cannabinoid-2 Receptor Ligands.

Journal of medicinal chemistry·2026
Same author

In-depth multimodal validation of <sup>18</sup>F-THK5351 for imaging monoamine oxidase-B-mediated reactive astrogliosis in Alzheimer's and related neurodegenerative diseases.

Experimental & molecular medicine·2026
Same author

Toward a Random Background for Ligand Optimization.

bioRxiv : the preprint server for biology·2026
Same author

The Selectivity Implications of Docking Libraries with Greater and Lesser Similarities to Bio-like Molecules.

Journal of medicinal chemistry·2026
Same author

Nuclear export as a therapeutic vulnerability in ZFTA-RELA ependymoma.

Neuro-oncology·2026

Area of Science:

  • Biochemistry
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • High-throughput screening (HTS) is crucial for early-stage drug discovery, but is hampered by promiscuous inhibitors.
  • Promiscuous inhibitors exhibit nonspecific activity across various targets, complicating screening results.
  • Existing explanations for promiscuity include chemical reactivity, assay interference, flexibility, and hydrophobicity.

Purpose of the Study:

  • To investigate a unified mechanism for promiscuous inhibition: the formation of enzyme-inhibiting colloidal aggregates.
  • To develop and validate rapid assays for detecting such promiscuous aggregates.
  • To evaluate computational models for predicting aggregate formation.

Main Methods:

  • Development of two rapid assays to detect colloidal aggregate formation in chemical compounds.

Related Experiment Videos

  • Testing of 1,030 'drug-like' molecules using the developed assays.
  • Validation of preliminary computational models against experimental assay data.

    • Main Results:

    • Identification of promiscuous aggregate formation as a potential unifying mechanism for inhibitors.
    • Demonstration that some compounds, including HTS hits and drugs, can act via aggregation at micromolar concentrations.
    • Establishment of experimental benchmarks for computational model development.

    Conclusions:

    • Colloidal aggregation represents a significant, potentially unified, mechanism underlying promiscuous inhibition in drug discovery.
    • The developed assays provide a practical tool for identifying and mitigating aggregate-forming compounds early in the drug discovery pipeline.
    • This work facilitates the development of more accurate computational models to predict and avoid promiscuous inhibitors.