[Show abstract][Hide abstract] ABSTRACT: The structure-guided optimisation of a hit series of chromone derivatives, previously identified using virtual screening of homology models of the adenosine A2A receptor, has led to the discovery of potent, selective and ligand efficient antagonists. Lipophilic hotspots and calculated water networks were modelled within the receptor binding site to facilitate rational ligand design.
Medicinal Chemistry Communication 05/2014; 5(5):571. DOI:10.1039/c3md00338h · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Virtual screening was performed against experimentally
homology models of the adenosine A2A receptor, identifying
a diverse range of ligand efficient antagonists (hit rate 9%). By
use of ligand docking and Biophysical Mapping (BPM), hits 1 and 5 were optimized to potent and selective lead molecules
(11–13 from 5, pKI = 7.5–8.5, 13- to >100-fold selective
versus adenosine A1; 14–16 from 1, pKI = 7.9–9.0,
19- to 59-fold selective).
[Show abstract][Hide abstract] ABSTRACT: Potent, ligand efficient, selective, and orally efficacious
derivatives have been identified using structure based drug design
approaches as antagonists of the adenosine A2A receptor.
The X-ray crystal structures of compounds 4e and 4g bound to the GPCR illustrate that the molecules bind deeply
inside the orthosteric binding cavity. In vivo pharmacokinetic and
efficacy data for compound 4k are presented, demonstrating
the potential of this series of compounds for the treatment of Parkinson’s
[Show abstract][Hide abstract] ABSTRACT: Methylxanthines, including caffeine and theophylline, are among the most widely consumed stimulant drugs in the world. These effects are mediated primarily via blockade of adenosine receptors. Xanthine analogs with improved properties have been developed as potential treatments for diseases such as Parkinson's disease. Here we report the structures of a thermostabilized adenosine A(2A) receptor in complex with the xanthines xanthine amine congener and caffeine, as well as the A(2A) selective inverse agonist ZM241385. The receptor is crystallized in the inactive state conformation as defined by the presence of a salt bridge known as the ionic lock. The complete third intracellular loop, responsible for G protein coupling, is visible consisting of extended helices 5 and 6. The structures provide new insight into the features that define the ligand binding pocket of the adenosine receptor for ligands of diverse chemotypes as well as the cytoplasmic regions that interact with signal transduction proteins.
[Show abstract][Hide abstract] ABSTRACT: G protein-coupled receptors (GPCRs) are one of the most important target classes in the central nervous system (CNS) drug discovery, however the fact they are integral membrane proteins and are unstable when purified out of the cell precludes them from a wide range of structural and biophysical techniques that are used for soluble proteins. In this study we demonstrate how protein engineering methods can be used to identify mutations which can both increase the thermostability of receptors, when purified in detergent, as well as biasing the receptor towards a specific physiologically relevant conformational state. We demonstrate this method for the adenosine A(2A) receptor and muscarinic M(1) receptor. The resultant stabilised receptors (known as StaRs) have a pharmacological profile consistent with the inverse agonist conformation. The stabilised receptors can be purified in large quantities, whilst retaining correct folding, thus generating reagents suitable for a broad range of structural and biophysical studies. In the case of the A(2A)-StaR we demonstrate that surface plasmon resonance can be used to profile the association and dissociation rates of a range of antagonists, a technique that can be used to improve the in vivo efficacy of receptor antagonists.