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Themed collection Phenotypic Drug Discovery

14 items
Review Article

The evolution of drug discovery: from phenotypes to targets, and back

Cumulative scientific and technological advances over the past two centuries have transformed drug discovery from a largely serendipitous process into the high tech pipelines of today.

Graphical abstract: The evolution of drug discovery: from phenotypes to targets, and back
From the themed collection: Phenotypic Drug Discovery
Review Article

Label-free technologies for target identification and validation

Chemical probes have been instrumental in revealing new targets and confirming target engagement. However, substantial effort and resources are required to design and synthesize these probes. In contrast, label-free technologies have the advantage of bypassing the need for chemical probes. Here we highlight the recent developments in label-free methods and discuss the pros and cons of each approach.

Graphical abstract: Label-free technologies for target identification and validation
From the themed collection: Phenotypic Drug Discovery
Concise Article

Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants

A screen of 20 compounds identified small molecule adjuvants capable of potentiating antibiotic activity against Francisella philomiragia.

Graphical abstract: Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants
From the themed collection: Phenotypic Drug Discovery
Concise Article

1,2,3-Dithiazoles – new reversible melanin synthesis inhibitors: a chemical genomics study

1,2,3-Dithiazolimines show potent and reversible inhibition of melanin synthesis in Xenopus laevis embryos.

Graphical abstract: 1,2,3-Dithiazoles – new reversible melanin synthesis inhibitors: a chemical genomics study
From the themed collection: Phenotypic Drug Discovery
Concise Article

Concise synthesis of spergualin-inspired molecules with broad-spectrum antibiotic activity

There is a growing need to identify new, broad-spectrum antibiotics. Here, we report a concise route to an antibiotic based on the privileged structure of the natural product spergualin.

Graphical abstract: Concise synthesis of spergualin-inspired molecules with broad-spectrum antibiotic activity
From the themed collection: Phenotypic Drug Discovery
Concise Article

Synthesis and biological evaluation of novel Δ2-isoxazoline fused cyclopentane derivatives as potential antimicrobial and anticancer agents

Novel Δ2-isoxazoline fused cyclopentane derivatives have been synthesized and evaluated for their antimicrobial and anticancer activities.

Graphical abstract: Synthesis and biological evaluation of novel Δ2-isoxazoline fused cyclopentane derivatives as potential antimicrobial and anticancer agents
From the themed collection: Phenotypic Drug Discovery
Open Access Concise Article

The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle

We demonstrate that the natural product brartemicin, a newly discovered inhibitor of cancer cell invasion, is a high-affinity ligand of the carbohydrate-recognition domain (CRD) of the C-type lectin mincle.

Graphical abstract: The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle
From the themed collection: Phenotypic Drug Discovery
Concise Article

Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria

The repurposing of human tyrosine kinase inhibitor scaffolds for generation of antiparasitic agents has provided new lead compounds for tropical diseases.

Graphical abstract: Evaluation of aromatic 6-substituted thienopyrimidines as scaffolds against parasites that cause trypanosomiasis, leishmaniasis, and malaria
From the themed collection: Phenotypic Drug Discovery
Concise Article

Synthetic spirocyclic endoperoxides: new antimalarial scaffolds

Design, synthesis and molecular docking calculation studies led to the identification of novel spirocyclic peroxides with in vitro and in vivo antimalarial activity.

Graphical abstract: Synthetic spirocyclic endoperoxides: new antimalarial scaffolds
From the themed collection: Phenotypic Drug Discovery
Open Access Research Article

Open PHACTS computational protocols for in silico target validation of cellular phenotypic screens: knowing the knowns

Six computational protocols to annotate phenotypic screens.

Graphical abstract: Open PHACTS computational protocols for in silico target validation of cellular phenotypic screens: knowing the knowns
From the themed collection: Phenotypic Drug Discovery
Research Article

In vivo phenotypic drug discovery: applying a behavioral assay to the discovery and optimization of novel antipsychotic agents

A mouse-based assay (SmartCube) was used for both screening and lead optimization of a novel antipsychotic.

Graphical abstract: In vivo phenotypic drug discovery: applying a behavioral assay to the discovery and optimization of novel antipsychotic agents
From the themed collection: Phenotypic Drug Discovery
Research Article

The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery

Paroxetine is a new anti-schistosomal lead with potent activity against schistosomula and adult life stages of S. mansoni.

Graphical abstract: The antidepressant drug paroxetine as a new lead candidate in schistosome drug discovery
From the themed collection: Phenotypic Drug Discovery
Research Article

Design, synthesis and anti-proliferative activities of novel 7′-O-substituted schisantherin A derivatives

A series of schisantherin A (1) derivatives were efficiently synthesized utilizing Yamaguchi esterification (2,4,6-trichlorobenzoyl chloride, Et3N, THF, DMAP, toluene) at the C-7′ position of the schisantherin A core.

Graphical abstract: Design, synthesis and anti-proliferative activities of novel 7′-O-substituted schisantherin A derivatives
From the themed collection: Phenotypic Drug Discovery
Research Article

Glabridin-chalcone hybrid molecules: drug resistance reversal agent against clinical isolates of methicillin-resistant Staphylococcus aureus

16 folds reduction in MICs with norfloxacin against various clinical isolates of MRSA (FICI range from 0.312–0.375).

Graphical abstract: Glabridin-chalcone hybrid molecules: drug resistance reversal agent against clinical isolates of methicillin-resistant Staphylococcus aureus
From the themed collection: Phenotypic Drug Discovery
14 items

About this collection

Phenotypic approaches are highly complementary to the molecular target centric strategy that prevails in Pharma and moreover, may mitigate future clinical failure issues related to target validation and lack of efficacy. Five years into the Phenotypic Drug Discovery (PDD) Renaissance, this special issue guest edited by Dr Fabien Vincent (Pfizer), Dr Jonathan Lee (Eli Lilly) and Professor Michael Pollastri (Northeastern University, USA) aims to shift the main focus in this area from assays and screens towards the medicinal chemistry programs engendered by these early efforts.

A broad variety of themes are present, testament to the multidisciplinary ecosystem supporting phenotypic drug discovery. These include drug repurposing, target identification, safety, natural product chemistry, polypharmacology, computational mechanism prediction, and development of structure activity relationships using a wide variety of biological/phenotypic systems, ranging from bacteria, parasites, and mammalian cells to mice.

Manuscripts covering the lessons learned and progress recorded on the road to clinical candidates were actively sought. Additionally, articles published recently in this journal were included based on relevance and novelty. Finally, links to articles of potential interest to readers from a recent special issue on Chemical Biology for Target Identification and Validation are also provided directly below.

Acyl protein thioesterase inhibitors as probes of dynamic S-palmitoylation
Dahvid Davda and Brent R. Martin, Review Article

Target validation using in-cell small molecule clickable imaging probes
Brahma Ghosh and Lyn H. Jones, Review Article

Affinity-based target identification for bioactive small molecules
Makoto Kawatani and Hiroyuki Osada , Review Article

Rapid profiling of protein kinase inhibitors by quantitative proteomics
Martin Golkowski, Jennifer L. Brigham, B. Gayani K. Perera, Guillermo S. Romano, Dustin J. Maly and Shao-En Ong , Concise Article

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