Identification of Novel Adenosine A_2A Receptor Antagonists by Virtual Screening

Abstract

Virtual screening was performed against experimentally enabled 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).

New Insights for Drug Design from the X-Ray Crystallographic Structures of G-Protein-Coupled Receptors

“…A number of controlled experiments targeting the ␤-adrenergic and adenosine receptors, conducted by subjecting to molecular docking known agonists and blockers together with a larger number of nonbinders, clearly illustrated that such virtual screening campaigns are most effective when applied to X-ray structures (Reynolds et , 2012). This observation is consistent with the successful identification of novel structurally diverse ligands on the basis of virtual screenings conducted by targeting the crystal structures of ␤-adrenergic, adenosine, dopamine, and histamine receptors (Sabio et al, 2008;Kolb et al, 2009;Carlsson et al, 2010Carlsson et al, , 2011Katritch et al, 2010a;de Graaf et al, 2011;van der Horst et al, 2011;Langmead et al, 2012). The above-mentioned controlled experiments also demonstrated that virtual screening campaigns, although not as effective as when applied to a crystal structure, are useful when applied to accurate homology models (Cavasotto et al, 2008;Katritch et al, 2010b;Phatak et al, 2010;Vilar et al, 2010Vilar et al, , 2011aCavasotto, 2011).…”

“…Then, molecular modeling and docking are used to map the small molecule-binding site with respect to each chemical class of ligands. This approach was used to identify novel chemotypes (later to be optimized by chemical modification), such as chromones and triazines, binding to the A 2A adenosine receptor Langmead et al, 2012).…”

Molecular Determinants of CGS21680 Binding to the Human Adenosine A2A Receptor

“…Subsequently, the structure of a thermostabilized version of A 2A R was determined, also with ZM241385 bound (PDB ID 3PWH; Dore et al, 2011), and the high similarity between the structures [root mean square deviation (RMSD) 0.6 Å for 284 residues and 1648 atoms aligned in PyMOL (Schrödinger, San Diego, CA)] showed that neither the thermostabilizing mutations nor the T4L fusion had any significant impact on the structure of the receptor (Tate, 2012). A total of 12 X-ray structures are now available for A 2A R, bound to the following ligands: inverse agonist ZM241385 (Jaakola et al, 2008;Dore et al, 2011;Hino et al, 2012); the full agonists adenosine (Lebon et al, 2011b), 59-N-ethylcarboxamido adenosine (NECA; Lebon et al, 2011b), and UK432097 [6-(2,2-diphenylethylamino)-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxy-tetrahydrofuran-2-yl]-N-[2-[[1-(2-pyridyl)-4-piperidyl]carbamoylamino]ethyl]purine-2-carboxamide] (Xu et al, 2011); the neutral antagonists caffeine and xanthine amine congener (Dore et al, 2011); and to novel compounds developed as preclinical candidates for the treatment of Parkinson's disease Langmead et al, This work was funded in part by a grant from Heptares Therapeutics Ltd. and core funding from the Medical Research Council [Grant MRC U105197215]. Guillaume Lebon was funded by the program CNRS ATIP-AVENIR.…”

Pharmacology and Structure of Isolated Conformations of the Adenosine A2AReceptor Define Ligand Efficacy

“…Using the StaR method, active-state (GL0, GL23, GL26, and GL31) and inactive-state (StaR2) adenosine A 2A StaRs have been engineered, allowing solving of crystal structures of agonist-bound and inverse agonist-bound adenosine A 2A receptors (Dore et al, 2011;Lebon et al, 2011b). Recently, the benefit of structure-based drug design has been demonstrated at GPCRs with the adenosine A 2A crystal structure used to aid discovery of a novel chemical series of receptor antagonists Langmead et al, 2012).…”