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Ranking the selectivity of pubchem screening hits by activity-based protein profiling: MMP13 as a case study

Academic Article
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Overview

authors

  • Nakai, R.
  • Salisbury, C. M.
  • Rosen, Hugh
  • Cravatt, Benjamin

publication date

  • February 2009

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • High-throughput screening (HTS) has become an integral part of academic and industrial efforts aimed at developing new chemical probes and drugs. These screens typically generate several 'hits', or lead active compounds, that must be prioritized for follow-up medicinal chemistry studies. Among primary considerations for ranking lead compounds is selectivity for the intended target, especially among mechanistically related proteins. Here, we show how the chemical proteomic technology activity-based protein profiling (ABPP) can serve as a universal assay to rank HTS hits based on their selectivity across many members of an enzyme superfamily. As a case study, four metalloproteinase-13 (MMP13) inhibitors of similar potency originating from a publically supported HTS and reported in PubChem were tested by ABPP for selectivity against a panel of 27 diverse metalloproteases. The inhibitors could be readily separated into two groups: (1) those that were active against several metalloproteases and (2) those that showed high selectivity for MMP13. The latter set of inhibitors was thereby designated as more suitable for future medicinal chemistry optimization. We anticipate that ABPP will find general utility as a platform to rank the selectivity of lead compounds emerging from HTS assays for a wide variety of enzymes.

subject areas

  • Combinatorial Chemistry Techniques
  • Databases, Factual
  • Drug Design
  • Drug Evaluation, Preclinical
  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinases, Secreted
  • Pilot Projects
  • Protease Inhibitors
  • Structure-Activity Relationship
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Research

keywords

  • Activity-based profiling
  • Enzymes
  • High-throughput screening
  • Inhibitors
  • Metalloproteinase
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Identity

PubMed Central ID

  • PMC2661618

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2008.03.018

PubMed ID

  • 18364257
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Additional Document Info

start page

  • 1101

end page

  • 1108

volume

  • 17

issue

  • 3

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