Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery

@article{Jung2015TargetDO,
  title={Target deconvolution of bioactive small molecules: the heart of chemical biology and drug discovery},
  author={Hye Jin Jung and Ho Jeong Kwon},
  journal={Archives of Pharmacal Research},
  year={2015},
  volume={38},
  pages={1627-1641}
}
  • H. Jung, H. Kwon
  • Published 2015
  • Biology, Medicine
  • Archives of Pharmacal Research
Identification of the target proteins of bioactive small molecules isolated from phenotypic screens plays an important role in chemical biology and drug discovery. However, discovering the targets of small molecules is often the most challenging and time-consuming step for chemical biology researchers. To overcome the bottlenecks in target identification, many new approaches based on genomics, proteomics, and bioinformatics technologies have been developed. Here, we provide an overview of the… Expand
Target identification for biologically active small molecules using chemical biology approaches
TLDR
Current procedures for target identification are discussed, the most recent target identification approaches are reviewed, and several examples that illustrate advanced target identification technology are presented. Expand
Structure-Based Kinase Profiling To Understand the Polypharmacological Behavior of Therapeutic Molecules
TLDR
A computational pipeline, based on reverse virtual screening technique using several consensus scoring strategies, and structure-based kinase profiling of 12 FDA-approved drugs is demonstrated and experimentally validated that mahanine is able to modulate multiple kinases that are involved in cross-talk with different signaling molecules, which thereby exhibits its polypharmacological action. Expand
Identification of Protein Targets of Bioactive Small Molecules Using Randomly Photomodified Probes.
TLDR
This work presents a method for stochastic modification of small molecules of interest with a photoactivatable phenyldiazirine linker and validated this approach using known inhibitors of several medicinally relevant enzymes. Expand
Advances in identification and validation of protein targets of natural products without chemical modification.
TLDR
This review focuses on and reports case studies of the latest advances in target protein identification methods for label-free natural products, including drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation, cellular thermal shift assay (CETSA), thermal proteome profiling (TPP), and bioinformatics-based analysis of connectivity. Expand
Chemoproteomic characterization of covalent target engagement in cells
Compound attrition is one of the main reasons for the increasing costs of drug discovery projects. Many candidate drug molecules fail because they do not reach the site of action, the target is notExpand
Profiling the Protein Targets of Unmodified Bio‐Active Molecules with Drug Affinity Responsive Target Stability and Liquid Chromatography/Tandem Mass Spectrometry
TLDR
This review highlights recent proteomic approaches utilizing data‐dependent analysis and data‐independent analysis to identify target proteins by DARTS, and an effective strategy is proposed for selecting the target protein(s) from within the pool of analyzed candidates. Expand
A New Metric Quantifying Chemical and Biological Property of Small Molecule Metabolites and Drugs
TLDR
By applying NBE to the DrugBank CSMs whose properties are largely known, it is revealed that NBE is able to describe a number of critical druggable properties including logP, pKa, membrane permeability, blood–brain barrier penetration, and human intestinal absorption. Expand
Chemical Proteomic Approaches Targeting Cancer Stem Cells: A Review of Current Literature.
  • H. Jung
  • Biology, Medicine
  • Cancer genomics & proteomics
  • 2017
TLDR
This review provides an overview of major methodologies utilized in chemical proteomic approaches and future direction of potential CSC research by integrating chemical genomic and proteomic data obtained from a single biological sample of CSCs are suggested. Expand
Natural Products for Drug Discovery in the 21st Century: Innovations for Novel Drug Discovery
TLDR
This review discusses plant-based natural product drug discovery and how innovative technologies play a role in next-generation drug discovery. Expand
Membrane-Based Affinity Purification to Identify Target Proteins of a Small-Molecule Drug.
TLDR
Comparison of affinity capture using membranes, Affi-Gel 10 resin or M-270 Dynabeads derivatized with AEBSA suggests that only membranes allow identification of low-abundance CAII as a target, and shows that the spiked CAII is the only protein with a log2 ratio consistently >2. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 101 REFERENCES
Identification of Direct Protein Targets of Small Molecules
TLDR
The DARTS method is reviewed, why it works, and new perspectives for future development in this area are provided. Expand
Discovery of new small molecules and targets towards angiogenesis via chemical genomics approach.
  • H. Kwon
  • Chemistry, Medicine
  • Current drug targets
  • 2006
TLDR
This work has applied chemical genomics to angiogenesis, a new blood vessel formation, resulting in the identification of new small molecules as well as targets, and its application towards a cellular phenotype, angiogenic, will be demonstrated. Expand
Identification and validation of bioactive small molecule target through phenotypic screening.
TLDR
The combination of phenotypic screening in combination with multi-omics-based target identification and validation will provide an effective approach to discover new bioactive small molecules and their target protein and mechanism identification. Expand
Proteomic methods for drug target discovery.
TLDR
Significant progress has been made in this rapidly advancing field, speeding the clinical validation of drug candidates and the discovery of the novel targets for lead compounds developed using cell-based phenotypic screens. Expand
Target identification of small molecules based on chemical biology approaches.
TLDR
Recent progress in both affinity-based (direct) and phenotypic profiling (indirect) approaches for chemical biology target identification are described and summarized. Expand
Target identification and mechanism of action in chemical biology and drug discovery.
TLDR
This work focuses on target-identification and mechanism-of-action studies, which allow small-molecule action to be tested in a more disease-relevant setting at the outset, but require follow-up studies to determine the precise protein target or targets responsible for the observed phenotype. Expand
Towards high-throughput characterization of small molecule mechanisms of action.
  • H. Luesch
  • Biology, Medicine
  • Molecular bioSystems
  • 2006
TLDR
Current methodologies and technologies are discussed, including how these global approaches complement affinity-based target identification strategies. Expand
Target identification for small bioactive molecules: finding the needle in the haystack.
TLDR
Current methods for target identification of small molecules are summarized, primarily for a chemistry audience but also the biological community, for example, the chemist or biologist attempting to identify the target of a given bioactive compound. Expand
Identification and characterization of molecular targets of natural products by mass spectrometry.
TLDR
An overview on the applications of mass spectrometry-based techniques in the identification and characterization of natural product-protein interactions, and how these applications might revolutionizenatural product-based drug discovery is provided. Expand
Ion Channels as Drug Targets: The Next GPCRs
TLDR
Together, these methodologies, along with classical drug development practices, provide an opportunity to discover and optimize the activity of ion channel drug development candidates. Expand
...
1
2
3
4
5
...