The utility of target-based discovery

Croston, Glenn

doi:10.1080/17460441.2017.1308351

Cited by 90 publications

(86 citation statements)

References 14 publications

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“…In contrast, the targets in the target-based approach are well defined. With the molecular target in hand, discovery of novel binders can be facilitated by utilizing crystallographic and biochemical studies, computational modeling, binding kinetics, and mutational analysis to gain insight into how the target and the ligand interact and thus enable efficient structure-activity (SAR) analysis and the development of future generations of binders [26].…”

Section: Combinatorial Peptide Librariesmentioning

confidence: 99%

Evolving a Peptide: Library Platforms and Diversification Strategies

Bozovičar

Bratkovič

2019

IJMS

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Peptides are widely used in pharmaceutical industry as active pharmaceutical ingredients, versatile tools in drug discovery, and for drug delivery. They find themselves at the crossroads of small molecules and proteins, possessing favorable tissue penetration and the capability to engage into specific and high-affinity interactions with endogenous receptors. One of the commonly employed approaches in peptide discovery and design is to screen combinatorial libraries, comprising a myriad of peptide variants of either chemical or biological origin. In this review, we focus mainly on recombinant peptide libraries, discussing different platforms for their display or expression, and various diversification strategies for library design. We take a look at well-established technologies as well as new developments and future directions.

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Section: Combinatorial Peptide Librariesmentioning

confidence: 99%

Evolving a Peptide: Library Platforms and Diversification Strategies

Bozovičar

Bratkovič

2019

IJMS

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“…Before diving into recent advances in technology, we briefly describe the early stage of drug discovery in a historical perspective. Two crucial types of screening methods were pioneered and developed in the 1980s: target-based screens, which focus on a specific protein of interest reviewed by Croston (2017), and phenotypic screens, which concentrate on the disease state to be treatedreviewed by Wagner (2016). Target-based high-throughput screening (HTS) strategies for drug discovery kicked off in the early 1980s (Pereira & Williams, 2007) (Fig.…”

Section: Evolution Of Screening Technologies For Drug Discoverymentioning

confidence: 99%

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

Veggiani

Gerpe

Sidhu

et al. 2019

Pharmacology & Therapeutics

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a b s t r a c t a r t i c l e i n f o Development of effective cancer therapeutic strategies relies on our ability to interfere with cellular processes that are dysregulated in tumors. Given the essential role of the ubiquitin proteasome system (UPS) in regulating a myriad of cellular processes, it is not surprising that malfunction of UPS components is implicated in numerous human diseases, including many types of cancer. The clinical success of proteasome inhibitors in treating multiple myeloma has further stimulated enthusiasm for targeting UPS proteins for pharmacological intervention in cancer treatment, particularly in the precision medicine era. Unfortunately, despite tremendous efforts, the paucity of potent and selective UPS inhibitors has severely hampered attempts to exploit the UPS for therapeutic benefits. To tackle this problem, many groups have been working on technology advancement to rapidly and effectively screen for potent and specific UPS modulators as intracellular probes or early-phase therapeutic agents. Here, we review several emerging technologies for developing chemical-and protein-based molecules to manipulate UPS enzymatic activity, with the aim of providing an overview of strategies available to target ubiquitination for cancer therapy.

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“…Target identification is the key value of TDD [6]. With the target protein in hand, detailed drug-protein characterization is possible and this provides a better understanding of structure-activity relationships, which is a challenge in phenotypic screening without a known target [11].…”

Section: Introductionmentioning

confidence: 99%

A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466

et al. 2020

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In recent years, there has been a revival of interest in phenotypic-based drug discovery (PDD) due to target-based drug discovery (TDD) falling below expectations. Both PDD and TDD have their unique advantages and should be used as complementary methods in drug discovery. The PhenoTarget approach combines the strengths of the PDD and TDD approaches. Phenotypic screening is conducted initially to detect cellular active components and the hits are then screened against a panel of putative targets. This PhenoTarget protocol can be equally applied to pure compound libraries as well as natural product fractions. Here we described the use of the PhenoTarget approach to identify an anti-tuberculosis lead compound. Fractions from Polycarpa aurata were identified with activity against Mycobacterium tuberculosis H37Rv. Native magnetic resonance mass spectrometry (MRMS) against a panel of 37 proteins from Mycobacterium proteomes showed that a fraction from a 95% ethanol re-extraction specifically formed a protein-ligand complex with Rv1466, a putative uncharacterized Mycobacterium tuberculosis protein. The natural product responsible was isolated and characterized to be polycarpine. The molecular weight of the ligand bound to Rv1466, 233 Da, was half the molecular weight of polycarpine less one proton, indicating that polycarpine formed a covalent bond with Rv1466.

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The utility of target-based discovery

Cited by 90 publications

References 14 publications

Evolving a Peptide: Library Platforms and Diversification Strategies

Evolving a Peptide: Library Platforms and Diversification Strategies

Emerging drug development technologies targeting ubiquitination for cancer therapeutics

A Phenotarget Approach for Identifying an Alkaloid Interacting with the Tuberculosis Protein Rv1466

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