Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A<sub>2A</sub> receptor

Andrews, Stephen P.; Tehan, Benjamin G.

doi:10.1039/c2md20164j

Cited by 25 publications

(16 citation statements)

References 98 publications

(182 reference statements)

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“…Synchrotron radiation has been critical in obtaining the first structures of GPCRs and has been employed in the fast follow-up of SBDD exploiting these targets and other related members of this large target class [18][19][20]. Structural biology of this class of target has primarily been exploited by two biotechnology companies, Heptares Therapeutics and Receptos, both of which have SBDD of GPCRs as a key component of their business model and, as a consequence, use synchrotrons extensively ( figure 3).…”

Section: Current and Future Challengesmentioning

confidence: 99%

Diamond: shedding light on structure-based drug discovery

Brown

Shotton

2015

Phil. Trans. R. Soc. A.

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Structure-based drug design has become a key tool for the development of novel drugs. The process involves elucidating the three-dimensional structure of the potential drug molecule bound to the target protein that has been identified as playing a key role in the disease state. Using this three-dimensional information facilitates the process of making improvements to the potential drug molecule by highlighting existing and possible new interactions within the binding site. This knowledge is used to inform increases in potency and selectivity of the molecules as well as to help improve other drug-like properties. The speed and numbers of samples that can be studied, combined with the improved resolution of the structures that can be obtained using synchrotron radiation, have had a significant impact on the utilization of crystallography in the drug discovery process.

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Section: Current and Future Challengesmentioning

confidence: 99%

Diamond: shedding light on structure-based drug discovery

Brown

Shotton

2015

Phil. Trans. R. Soc. A.

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“…7.4) Congreve et al 2012). Both receptor model construction as ligand optimization was driven by experimental (mutagenesis/biophysical mapping (Zhukov et al 2011) of receptor-ligand interaction hotspots) and computational analysis (identification of thermodynamically unstable water molecules that can be displaced by the ligand) Congreve et al 2012;Andrews and Benjamin 2013).…”

Section: (Ref)mentioning

confidence: 99%

“…Further substitutions yielded amongst others a highly potent (pKi D 9.0) and highly selective (59-fold over AA1R) compound (10b) by introducing a nmethylpiperazine moiety. Optimization of these triazine compounds (10a and 10b) was continued in a rational structure-based optimization study Andrews and Benjamin 2013). Instead of 1,3,5-triazines derivatives, 1,2,4-triazine derivatives were further explored by combined SPR, SDM, in silico binding mode studies and in silico thermodynamic stability calculations of water molecules.…”

Section: Optimization Of Virtual Screening Hitsmentioning

confidence: 99%

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

Kooistra¹,

Leurs²,

Esch³

et al. 2013

Advances in Experimental Medicine and Biology

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This chapter will focus on G protein-coupled receptor structure-based virtual screening and ligand design. A generic virtual screening workflow and its individual elements will be introduced, covering amongst others the use of experimental data to steer the virtual screening process, ligand binding mode prediction, virtual screening for novel ligands, and rational structure-based virtual screening hit optimization. An overview of recent successful structure-based ligand discovery and design studies shows that receptor models, despite structural inaccuracies, can be efficiently used to find novel ligands for GPCRs. Moreover, the recently solved GPCR crystal structures have further increased the opportunities in structure-based ligand discovery for this pharmaceutically important protein family. The current chapter will discuss several challenges in rational ligand discovery based on GPCR structures including: (i) structure-based identification of ligands with specific effects on GPCR mediated signaling pathways, and (ii) virtual screening and structure-based optimization of fragment-like molecules.

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“…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). Not only more refractory to downstream signal interference compared to biological assays, biophysical techniques in theory could provide structural or kinetic information on ligand binding that could contribute to efficient hit validation and evaluation.…”

Section: Biophysical Screeningmentioning

confidence: 99%

“…In theory, combination of TINS with 19 F NMR spectroscopy could yield a method of improved throughput and detection sensitivity to be applied for screening reasonable size fragment libraries against GPCRs and other membrane targets. Yet another novel method, preliminary data on capillary electrophoresis point at the potential of upcoming developments of this analytical technique aiming at screening of fragment ligands (35).…”

Section: Expert Opinionmentioning

confidence: 99%

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

Visegrády

Keserü

2013

Expert Opinion on Drug Discovery

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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

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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor

Cited by 25 publications

References 98 publications

Diamond: shedding light on structure-based drug discovery

Diamond: shedding light on structure-based drug discovery

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

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

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Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A2A receptor

Cited by 25 publications

References 98 publications

Diamond: shedding light on structure-based drug discovery

Diamond: shedding light on structure-based drug discovery

From Three-Dimensional GPCR Structure to Rational Ligand Discovery

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

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Product

Resources

About

Stabilised G protein-coupled receptors in structure-based drug design: a case study with adenosine A_2A receptor