scholarly journals From Phenotypic Hit to Chemical Probe: Chemical Biology Approaches to Elucidate Small Molecule Action in Complex Biological Systems

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5702
Author(s):  
Quentin T. L. Pasquer ◽  
Ioannis A. Tsakoumagkos ◽  
Sascha Hoogendoorn
Keyword(s):  
Small Molecules ◽  
Chemical Biology ◽  
Target Identification ◽  
Biologically Active ◽  
Phenotypic Screening ◽  
Biological Processes ◽  
Chemical Probes ◽  
Target Deconvolution ◽  
Cellular Target ◽  
Screening Approaches

Biologically active small molecules have a central role in drug development, and as chemical probes and tool compounds to perturb and elucidate biological processes. Small molecules can be rationally designed for a given target, or a library of molecules can be screened against a target or phenotype of interest. Especially in the case of phenotypic screening approaches, a major challenge is to translate the compound-induced phenotype into a well-defined cellular target and mode of action of the hit compound. There is no “one size fits all” approach, and recent years have seen an increase in available target deconvolution strategies, rooted in organic chemistry, proteomics, and genetics. This review provides an overview of advances in target identification and mechanism of action studies, describes the strengths and weaknesses of the different approaches, and illustrates the need for chemical biologists to integrate and expand the existing tools to increase the probability of evolving screen hits to robust chemical probes.

scholarly journals Development of a chemogenomics library for phenotypic screening

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Bryan Dafniet ◽  
Natacha Cerisier ◽  
Batiste Boezio ◽  
Anaelle Clary ◽  
Pierre Ducrot ◽  
...  
Keyword(s):  
Small Molecules ◽  
Drug Target ◽  
Drug Targets ◽  
Chemical Biology ◽  
Target Identification ◽  
Biological Effects ◽  
Phenotypic Screening ◽  
High Content Imaging ◽  
Advanced Technologies ◽  
System Pharmacology

AbstractWith the development of advanced technologies in cell-based phenotypic screening, phenotypic drug discovery (PDD) strategies have re-emerged as promising approaches in the identification and development of novel and safe drugs. However, phenotypic screening does not rely on knowledge of specific drug targets and needs to be combined with chemical biology approaches to identify therapeutic targets and mechanisms of actions induced by drugs and associated with an observable phenotype. In this study, we developed a system pharmacology network integrating drug-target-pathway-disease relationships as well as morphological profile from an existing high content imaging-based high-throughput phenotypic profiling assay known as “Cell Painting”. Furthermore, from this network, a chemogenomic library of 5000 small molecules that represent a large and diverse panel of drug targets involved in diverse biological effects and diseases has been developed. Such a platform and a chemogenomic library could assist in the target identification and mechanism deconvolution of some phenotypic assays. The usefulness of the platform is illustrated through examples.

scholarly journals Target Identification of Compounds from a Cell Viability Phenotypic Screen Using a Bead/Lysate-Based Affinity Capture Platform

2015 ◽  
Vol 21 (2) ◽  
pp. 201-211 ◽  
Author(s):  
Hua Tang ◽  
Shannon Duggan ◽  
Paul L. Richardson ◽  
Violeta Marin ◽  
Scott E. Warder ◽  
...  
Keyword(s):  
Target Identification ◽  
Hdac Inhibitors ◽  
Affinity Capture ◽  
Target Deconvolution ◽  
Phenotypic Screen ◽  
A Cell ◽  
Bona Fide ◽  
Drug Leads ◽  
Target Diversity ◽  
Screening Approaches

The pharmaceutical industry has been continually challenged by dwindling target diversity. To obviate this trend, phenotypic screens have been adopted, complementing target-centric screening approaches. Phenotypic screens identify drug leads using clinically relevant and translatable mechanisms, remaining agnostic to targets. While target anonymity is advantageous early in the drug discovery process, it poses challenges to hit progression, including the development of backup series, retaining desired pharmacology during optimization, discovery of markers, and understanding mechanism-driven toxicity. Consequently, significant effort has been expended to elaborate the targets and mechanisms at work for promising screening hits. Affinity capture is commonly leveraged, where the compounds are linked to beads and targets are abstracted from cell homogenates. This technique has proven effective for identifying targets of kinase, PARP, and HDAC inhibitors, and examples of new targets have been reported. Herein, a three-pronged approach to target deconvolution by affinity capture is described, including the implementation of a uniqueness index that helps discriminate between bona fide targets and background. The effectiveness of this approach is demonstrated using characterized compounds that act on known and noncanonical target classes. The platform is subsequently applied to phenotypic screening hits, identifying candidate targets. The success rate of bead-based affinity capture is discussed.

scholarly journals Current Synthetic Routes to Peptidyl Mono-Fluoromethyl Ketones (FMKs) and Their Applications

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5601
Author(s):  
Carissa M. Lloyd ◽  
Neil Colgin ◽  
Steven L. Cobb
Keyword(s):  
Protease Inhibitors ◽  
Chemical Biology ◽  
Medicinal Chemistry ◽  
Biologically Active ◽  
Solution Phase ◽  
Chemical Probes ◽  
Cellular Processes ◽  
Synthetic Routes

Peptidyl mono-fluoromethyl ketones (FMKs) are a class of biologically active molecules that show potential as both protease inhibitors for the treatment of a range of diseases and as chemical probes for the interrogation of cellular processes. This review describes the current solid- and solution-phase routes employed for the synthesis of peptidyl mono-FMKs. In addition, it provides a brief overview of some of the key applications of FMKs in the fields of chemical biology and medicinal chemistry.

Target identification of small molecules based on chemical biology approaches

2013 ◽  
Vol 9 (5) ◽  
pp. 897 ◽  
Author(s):  
Yushi Futamura ◽  
Makoto Muroi ◽  
Hiroyuki Osada
Keyword(s):  
Small Molecules ◽  
Chemical Biology ◽  
Target Identification

Natural products-prompted chemical biology: phenotypic screening and a new platform for target identification

2016 ◽  
Vol 33 (5) ◽  
pp. 648-654 ◽  
Author(s):  
Hideaki Kakeya
Keyword(s):  
Cell Membrane ◽  
Cancer Cells ◽  
Chemical Biology ◽  
Target Identification ◽  
Chemical Genetics ◽  
Phenotypic Screening ◽  
Cancer Microenvironment ◽  
Microbial Metabolites ◽  
Cellular Targets ◽  
Target Cancer

This highlight focuses on our recent discoveries and chemical genetics approaches for bioactive microbial metabolites that target cancer cells, the cancer microenvironment, and cell membrane signalling. In addition, the development of two new platforms to identify the cellular targets of these molecules is also discussed.

Drug target prediction using chem- and bioinformatics

2018 ◽  
Vol 3 (12) ◽  
Author(s):  
Rita C. Guedes ◽  
Tiago Rodrigues
Keyword(s):  
Drug Target ◽  
Chemical Biology ◽  
Target Identification ◽  
Target Prediction ◽  
Molecular Medicine ◽  
The Poor ◽  
Target Deconvolution ◽  
Phenotypic Screen ◽  
Powerful Means ◽  
Drug Target Prediction

Abstract The biological pre-validation of natural products (NPs) and their underlying frameworks ensures an unrivaled source of inspiration for chemical probe and drug design. However, the poor knowledge of their drug target counterparts critically hinders the broader exploration of NPs in chemical biology and molecular medicine. Cutting-edge algorithms now provide powerful means for the target deconvolution of phenotypic screen hits and generate motivated research hypotheses. Herein, we present recent progress in artificial intelligence applied to target identification that may accelerate future NP-inspired molecular medicine.

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