Fragment Screening of Stabilized G-Protein-Coupled Receptors Using Biophysical Methods

Congreve, Miles; Rich, Rebecca L.; Myszka, David G.; Figaroa, Francis; Siegal, Gregg; Marshall, Fiona H.

doi:10.1016/b978-0-12-381274-2.00005-4

Cited by 107 publications

(111 citation statements)

References 22 publications

Supporting

Mentioning

104

Contrasting

Order By: Relevance

“…Approximately 10% of the screened compounds were found active in our fragment screen for α 2C receptor agonists. This active rate, although much higher than under conventional HTS settings, is comparable to those reported for GPCRs using diverse assays as TINS, SPR, 10 intact cell binding 14 and conventional biochemical screening. 16,17 24% of confirmed hits were found to prefer α 2C over an unrelated target, and 76% of these displayed significant activity in a biochemical assay as well.…”

Section: Discussionsupporting

confidence: 65%

“…While for soluble targets numerous successful FBDD programs are documented, 1,9 reports on fragment screening for membrane proteins are much sparser. SPR was applied successfully using immobilized and tagged membrane proteins [10][11][12] while researchers from Heptares and ZoBio reported the use of target immobilized NMR screening (TINS) on thermostabilized GPCRs. 10,13 A novel adenosine A 3 receptor specific fluorescent label enabled development of a fluorescence intensity-based whole cell binding assay 14 capable of identifying low affinity ligands of A 3 .…”

Section: Introductionmentioning

confidence: 99%

“…SPR was applied successfully using immobilized and tagged membrane proteins [10][11][12] while researchers from Heptares and ZoBio reported the use of target immobilized NMR screening (TINS) on thermostabilized GPCRs. 10,13 A novel adenosine A 3 receptor specific fluorescent label enabled development of a fluorescence intensity-based whole cell binding assay 14 capable of identifying low affinity ligands of A 3 . Apart from these successful examples, where challenging targetspecific preparations were crucial for the actual screening process, some experiences with more generic assay formats for probing membrane proteins have been reported as well.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Cell-based and virtual fragment screening for adrenergic α2C receptor agonists

Szollosi

Bobok

Kiss

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Cell-based and virtual fragment screening for adrenergic α2C receptor agonists

Szollosi

Bobok

Kiss

et al. 2015

Bioorganic & Medicinal Chemistry

View full text Add to dashboard Cite

“…NMR spectroscopy as well as X-ray crystallography allow for direct and sensitive detection of ligand-target interaction less prone to downstream artifacts of detection (33), but historically GPCRs, just like other membrane targets, fell out of scope of structure-based approaches. Owing to very recent achievements in stabilization techniques of membrane proteins as well as direct detection methods to monitor low affinity interactions GPCRs became accessible for biophysical detection techniques (12,34). The advent of this approach was demonstrated by successful structure-based drug discovery on a GPCR under industrial settings (35).…”

Section: Biophysical Screeningmentioning

confidence: 99%

“…Recently, significant advance has been achieved in structural investigation methods of GPCRs as well as receptor stabilization and presentation techniques required for development of screening assays (11). Several very recent reports for as diverse techniques as NMR screening on immobilized receptors (12) to live cell binding studies (13) with the aim to identify and develop fragmentsize GPCR ligands have been reported. It is expected that wide spread application of fragment-based drug discovery to GPCR targets could provide novel chemical matter previously inaccessible for random screening.…”

Section: Introductionmentioning

confidence: 99%

Fragment-based lead discovery on G-protein-coupled receptors

Visegrády

Keserü

2013

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

KEYWORDS GPCR, fragment screening, virtual screening ARTICLE HIGHLIGHTS Recent advances in structural and biophysical characterization of GPCRs lead to improved efficacy of in vitro and in silico fragment-based lead discovery for GPCRs  Virtual fragment screening is a feasible approach for GPCR lead discovery  Multiple receptor conformations (including both experimental and theoretical models) might enhance the success rate of virtual fragment screening  Relevance of biophysical methods for fragment screening and evaluation on GPCRs has increased significantly  In vitro biological assays are suitable for functional screening on GPCRs 2 ABSTRACT Introduction G-protein-coupled receptors form one of the largest groups of potential targets for novel medications. Low druggability of many GPCR targets and inefficient sampling of chemical space in high throughput screening expertise however often hinder discovery of drug discovery leads for GPCRs. Fragment-based drug discovery is an alternative approach to the conventional strategy and has proven its efficiency on several enzyme targets. Based on developments in biophysical screening techniques, receptor stabilization and in vitro assays, virtual and experimental fragment screening and fragment-based lead discovery recently became applicable for GPCR targets.Areas covered Biophysical as well as biological detection techniques suitable to study GPCRs are reviewed, together with their applications to screen fragment libraries and identify fragment-size ligands of cell surface receptors. Several recent examples are presented, including both virtual and experimental protocols for fragment hit discovery and early hit to lead progress. Expert opinionWith the recent progress in biophysical detection techniques the advantages of fragmentbased drug discovery could be exploited for GPCR targets. Structural information on GPCRs will be more abundantly available for early stages of drug discovery projects, providing information on the binding process and efficiently supporting the progression of fragment hit to lead. In silico approaches in combination with biological assays can be used to address structurally challenging GPCRs and confirm biological relevance of interaction early in the drug discovery project.3

show abstract

The Role of Chemical Biology in Drug Discovery

Pope

2012

Wiley Encyclopedia of Chemical Biology

View full text Add to dashboard Cite

Chemical biology methods are central to the discovery of new medicines. The development of new approaches and techniques has accompanied, and been central to, major advances in understanding of disease biology and a move from pharmacology‐driven to molecular‐medicine‐based drug discovery. This article will highlight some critical contributions from chemical biology methods in the context of a high‐level overview of drug discovery as practiced currently.

show abstract

Fragment Screening of Stabilized G-Protein-Coupled Receptors Using Biophysical Methods

Cited by 107 publications

References 22 publications

Cell-based and virtual fragment screening for adrenergic α2C receptor agonists

Cell-based and virtual fragment screening for adrenergic α2C receptor agonists

Fragment-based lead discovery on G-protein-coupled receptors

The Role of Chemical Biology in Drug Discovery

Contact Info

Product

Resources

About