Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

Promise of Structure-Based Drug Design for GPCRs

Published: Thursday, May 10, 2012
Last Updated: Thursday, May 10, 2012
Bookmark and Share
Heptares Therapeutics announces the recent publication of a major review of the state of the art for GPCR drug discovery and new insights that, for the first time, can be obtained from structural biology.

The review has been published online in Trends in Pharmacological Sciences, a Cell Press publication, and will appear in a special issue of the journal in May, which focuses on structure-based drug design (SBDD).

The authors from Heptares describe how SBDD is becoming the new paradigm for drug discovery targeting GPCRs due to recent technological developments in GPCR stabilisation and novel structural biology. Previously, such approaches were only applicable to soluble enzymes (such as kinases), for which they have now become integrated into the best practices of medicinal chemists. The success of SBDD in developing superior drugs targeting these enzymes has had a significant impact on the pipelines of pharmaceutical companies, leading to the development of multiple marketed drugs and late-stage pipeline candidates.

"The promise of SBDD for GPCRs is that rational design can now be used to identify and optimise ligands that bind challenging or undruggable GPCR targets," said Fiona Marshall, Heptares' Chief Scientific Officer and co-author of the paper. "These small molecules have the potential to offer better potency, selectivity and drug-like properties than previously achievable, establishing a strong basis for the development of much improved medicines for patients."

In the review, the authors discuss how the recent availability of X-ray structures of GPCRs in multiple pharmacologically relevant and ligand-bound conformations, and the subsequent computational analyses of the ligand-binding sites in these conformations, provide a new way to assess the druggability of GPCRs. Druggability is the property of a drug target describing the ease with which a satisfactory small molecule drug may be found which modulates that target in the desired manner. It is a key factor in prioritization of drug discovery targets.

As an example of this, the authors describe Heptares' recent work on the SBDD of A2A antagonists, illustrating how small, potent and selective compounds can be discovered and optimised using virtual screening and receptor-ligand models and X-ray co-structures. A deep druggable region of the A2A binding site revealed by crystallography was targeted and fully exploited to design orally available and efficacious antagonists. A lead candidate in this series is the subject of a global licensing agreement recently announced between Heptares and Shire.

To date, Heptares has applied its GPCR-focused SBDD approach to several other important GPCRs, enabling the assembly of a rich pipeline of novel drug candidates targeting serious neurological (CNS) and metabolic disorders, including: highly selective muscarinic M1 agonists (Alzheimer's disease and cognitive impairment associated with other CNS disorders); dual orexin 1/2 antagonist (chronic insomnia); selective orexin 1 antagonist (addiction and compulsive disorders); allosteric modulators of mGluR5 (autism, Parkinson's disease, depression and anxiety); GLP-1 agonist (Type 2 diabetes); and CXCR-4 antagonists (cancer/HIV).

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,700+ scientific posters on ePosters
  • More than 3,800+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Heptares Solves First Family B GPCR Structure
Heptares Therapeutics has used its StaR® technology to solve entirely in-house the first structure of a Family B sub-class G protein-coupled receptor.
Tuesday, September 11, 2012
Scientific News
New Approach to Treating Heparin-induced Blood Disorder
A potential treatment for a serious clotting condition that can strike patients who receive heparin to treat or prevent blood clots may lie within reach by elucidating the structure of the protein complex at its root.
Escape Prevention
Studying flu virus structure brings us a step closer to a permanent vaccine.
Scientists Decode Structure at Root of Muscular Disease
Researchers at Rice University and Baylor College of Medicine have unlocked the structural details of a protein seen as key to treating a neuromuscular disease.
A Natural Light Switch
MIT scientists identify and map the protein behind a light-sensing mechanism.
First Complete Structural Study Of A Pegylated Protein
Significant data obtained at NUI Galway reports first crystal structure of a protein modified with a single PEG chain.
Cellular Contamination Pathway for Heavy Elements Identified
Berkeley Lab scientists find that an iron-binding protein can transport actinides into cells.
Structural Discoveries Could Aid in Better Drug Design
Scientists have uncovered the structural details of how some proteins interact to turn two different signals into a single integrated output.
New Mathematics Advances the Frontier of Macromolecular Imaging
Berkeley Lab’s M-TIP solves the reconstruction problem for fluctuation X-ray scattering.
Diamond Helps Develop New Way of Studying the Tiniest Microcrystals
Researchers have developed a new type of sample holder for ‘serial protein crystallography’.
Crystal Clear Images Uncover Secrets of Hormone Receptors
NIH researchers gain better understanding of how neuropeptide hormones trigger chemical reactions in cells.
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,700+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
3,800+ scientific videos