Direct and indirect approaches to identify drug modes of action

Lindsay B. Tulloch, Stefanie K. Menzies, Ross P. Coron, Matthew D. Roberts, Gordon J. Florence (Lead / Corresponding author), Terry K. Smith (Lead / Corresponding author)

Research output: Contribution to journalReview article

5 Citations (Scopus)

Abstract

Phenotypic assays are becoming increasingly more common among drug discovery practices, expanding drug target diversity as lead compounds identified through such screens are not limited to known targets. While increasing diversity is beneficial to the drug discovery process and the fight against disease, the unknown modes of action of new lead compounds can hamper drug discovery as, in most cases, the process of lead compound optimization is made difficult due to the unknown nature of the target; blindly changing substituents can prove fruitless due to the inexhaustible number of potential combinations, and it is therefore desirable to rapidly identify the targets of lead compounds developed through phenotypic screening. In addition, leads identified through target-based screening often have off-target effects that contribute towards drug toxicity, and by identifying those secondary targets, the drugs can be improved. However, the identification of a leads mode of action is far from trivial and now represents a major bottleneck in the drug discovery pipeline. This review looks at some of the recent developments in the identification of drug modes of action, focusing on phenotype-based methods using metabolomics, proteomics, transcriptomics, and genomics to detect changes in phenotype in response to the presence of the drug, and affinity-based methods using modified/unmodified drug as bait to capture and identify targets.

Original languageEnglish
Pages (from-to)9-22
Number of pages14
JournalIUBMB Life
Volume70
Issue number1
Early online date6 Dec 2017
DOIs
Publication statusPublished - Jan 2018

Fingerprint

Lead compounds
Drug Discovery
Pharmaceutical Preparations
Screening
Phenotype
Metabolomics
Genomics
Drug-Related Side Effects and Adverse Reactions
Proteomics
Toxicity
Assays
Pipelines
Lead

Keywords

  • Chromatography, Liquid/instrumentation
  • Drug Design
  • Drug Discovery
  • Genomics/instrumentation
  • High-Throughput Screening Assays
  • Humans
  • Metabolomics
  • Molecular Targeted Therapy/methods
  • Protein Binding
  • Proteome/genetics
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Tandem Mass Spectrometry/instrumentation

Cite this

Tulloch, L. B., Menzies, S. K., Coron, R. P., Roberts, M. D., Florence, G. J., & Smith, T. K. (2018). Direct and indirect approaches to identify drug modes of action. IUBMB Life, 70(1), 9-22. https://doi.org/10.1002/iub.1697
Tulloch, Lindsay B. ; Menzies, Stefanie K. ; Coron, Ross P. ; Roberts, Matthew D. ; Florence, Gordon J. ; Smith, Terry K. / Direct and indirect approaches to identify drug modes of action. In: IUBMB Life. 2018 ; Vol. 70, No. 1. pp. 9-22.
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Tulloch, LB, Menzies, SK, Coron, RP, Roberts, MD, Florence, GJ & Smith, TK 2018, 'Direct and indirect approaches to identify drug modes of action', IUBMB Life, vol. 70, no. 1, pp. 9-22. https://doi.org/10.1002/iub.1697

Direct and indirect approaches to identify drug modes of action. / Tulloch, Lindsay B.; Menzies, Stefanie K.; Coron, Ross P.; Roberts, Matthew D.; Florence, Gordon J. (Lead / Corresponding author); Smith, Terry K. (Lead / Corresponding author).

In: IUBMB Life, Vol. 70, No. 1, 01.2018, p. 9-22.

Research output: Contribution to journalReview article

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AU - Tulloch, Lindsay B.

AU - Menzies, Stefanie K.

AU - Coron, Ross P.

AU - Roberts, Matthew D.

AU - Florence, Gordon J.

AU - Smith, Terry K.

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Y1 - 2018/1

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AB - Phenotypic assays are becoming increasingly more common among drug discovery practices, expanding drug target diversity as lead compounds identified through such screens are not limited to known targets. While increasing diversity is beneficial to the drug discovery process and the fight against disease, the unknown modes of action of new lead compounds can hamper drug discovery as, in most cases, the process of lead compound optimization is made difficult due to the unknown nature of the target; blindly changing substituents can prove fruitless due to the inexhaustible number of potential combinations, and it is therefore desirable to rapidly identify the targets of lead compounds developed through phenotypic screening. In addition, leads identified through target-based screening often have off-target effects that contribute towards drug toxicity, and by identifying those secondary targets, the drugs can be improved. However, the identification of a leads mode of action is far from trivial and now represents a major bottleneck in the drug discovery pipeline. This review looks at some of the recent developments in the identification of drug modes of action, focusing on phenotype-based methods using metabolomics, proteomics, transcriptomics, and genomics to detect changes in phenotype in response to the presence of the drug, and affinity-based methods using modified/unmodified drug as bait to capture and identify targets.

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KW - Genomics/instrumentation

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KW - Metabolomics

KW - Molecular Targeted Therapy/methods

KW - Protein Binding

KW - Proteome/genetics

KW - Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

KW - Tandem Mass Spectrometry/instrumentation

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EP - 22

JO - IUBMB Life

JF - IUBMB Life

SN - 1521-6543

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Tulloch LB, Menzies SK, Coron RP, Roberts MD, Florence GJ, Smith TK. Direct and indirect approaches to identify drug modes of action. IUBMB Life. 2018 Jan;70(1):9-22. https://doi.org/10.1002/iub.1697