open access publication

Preprint, 2024

STREAMLINED PROTEOME-WIDE IDENTIFICATION OF DRUG TARGETS INDICATES ORGAN-SPECIFIC ENGAGEMENT

bioRxiv, Page 2024.02.08.578880, 10.1101/2024.02.08.578880

Contributors

Batth, Tanveer Singh 0000-0001-5346-4544 (Corresponding author) [1] Locard-Paulet, Marie 0000-0003-2879-9224 [1] [2] Doncheva, Nadezhda Tsankova 0000-0002-8806-6850 [1] Mendez, Blanca Lopez [1] Jensen, Lars Juhl 0000-0001-7885-715X [1] Olsen, Jesper Velgaard 0000-0002-4747-4938 (Corresponding author) [1]

Affiliations

  1. [1] University of Copenhagen
    2. [NORA names: KU University of Copenhagen; University; Denmark; Europe, EU; Nordic; OECD];
  2. [2] Institute of Pharmacology and Structural Biology
    3. [NORA names: France; Europe, EU; OECD]

Abstract

ABSTRACT Proteins are the primary targets of almost all small molecule drugs. However, even the most selectively designed drugs can potentially target several unknown proteins. Identification of potential drug targets can facilitate design of new drugs and repurposing of existing ones. Current state-of-the-art proteomics methodologies enable screening of thousands of proteins against a limited number of drug molecules. Here we report the development of a label-free quantitative proteomics approach that enables proteome-wide screening of small organic molecules in a scalable, reproducible, and rapid manner by streamlining the proteome integral solubility alteration (PISA) assay. We used rat organs ex-vivo to determine organ specific targets of medical drugs and enzyme inhibitors to identify novel drug targets for common drugs such as Ibuprofen. Finally, global drug profiling revealed overarching trends of how small molecules affect the proteome through either direct or indirect protein interactions.

Keywords

alterations, approach, design, development, drug, drug molecules, drug profile, drug targets, engagement, enzyme, enzyme inhibitors, ex vivo, ibuprofen, identification, identification of potential drug targets, indirect protein interactions, inhibitors, interaction, label-free quantitative proteomics approach, medical drugs, methodology, molecule drugs, molecules, organ-specific targeting, organic molecules, organization, organs ex vivo, potential drug targets, primary target, profile, protein, protein interactions, proteome integral solubility alteration, proteome-wide identification, proteome-wide screening, proteomic approach, proteomic methodologies, proteomics, quantitative proteomics approach, rats, repurposing, screening, small molecule drugs, small molecules, small organic molecules, specific targets, state-of-the-art, streamlines, target, trends, unknown proteins

Funders

  • Novo Nordisk Foundation
  • European Commission

Data Provider: Digital Science

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