Article pubs.acs.org/jmc Identification of Novel Adenosine A 2A Receptor Antagonists by Virtual Screening

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).

[1]  T. Engber,et al.  Synthesis of [1,2,4]triazolo[1,5-a]pyrazines as adenosine A2A receptor antagonists. , 2005, Bioorganic & medicinal chemistry letters.

[2]  A. Hopkins,et al.  Ligand efficiency: a useful metric for lead selection. , 2004, Drug discovery today.

[3]  Krzysztof Palczewski,et al.  Sequence analyses of G-protein-coupled receptors: similarities to rhodopsin. , 2003, Biochemistry.

[4]  T. Blundell,et al.  Comparative protein modelling by satisfaction of spatial restraints. , 1993, Journal of molecular biology.

[5]  P. Leeson,et al.  The influence of drug-like concepts on decision-making in medicinal chemistry , 2007, Nature Reviews Drug Discovery.

[6]  Ruben Abagyan,et al.  Structure-Based Discovery of Novel Chemotypes for Adenosine A 2 A Receptor Antagonists , 2010 .

[7]  D. E. Clark,et al.  Rapid calculation of polar molecular surface area and its application to the prediction of transport phenomena. 2. Prediction of blood-brain barrier penetration. , 1999, Journal of pharmaceutical sciences.

[8]  Ben M. Webb,et al.  Comparative Protein Structure Modeling Using Modeller , 2006, Current protocols in bioinformatics.

[9]  J. Thompson,et al.  CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. , 1994, Nucleic acids research.

[10]  Julian Blagg,et al.  Structural Alerts for Toxicity , 2010, Medicinal Chemistry for Practitioners.

[11]  Andrej Sali,et al.  Comparative Protein Structure Modeling Using MODELLER , 2014, Current protocols in bioinformatics.

[12]  C. Bundgaard,et al.  Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential. , 2010, Journal of medicinal chemistry.

[13]  G. Marucci,et al.  Adenosine receptor modeling: what does the A2A crystal structure tell us? , 2010, Current topics in medicinal chemistry.

[14]  A. Leslie,et al.  Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation , 2011, Nature.

[15]  C. Higgs,et al.  Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor. , 2010, ACS medicinal chemistry letters.

[16]  A. Pinna.  Novel investigational adenosine A2A receptor antagonists for Parkinson's disease , 2009, Expert opinion on investigational drugs.

[17]  K. Jacobson,et al.  Structure-activity relationships of 8-styrylxanthines as A2-selective adenosine antagonists. , 1993, Journal of medicinal chemistry.

[18]  J. Wess,et al.  Site-directed Mutagenesis Identifies Residues Involved in Ligand Recognition in the Human A2a Adenosine Receptor (*) , 1995, The Journal of Biological Chemistry.

[19]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[20]  X. García‐Mera,et al.  Pyrimidine derivatives as potent and selective A3 adenosine receptor antagonists. , 2011, Journal of medicinal chemistry.

[21]  Jonathan S. Mason,et al.  Progress in Structure Based Drug Design for G Protein-Coupled Receptors , 2011, Journal of medicinal chemistry.

[22]  A Sali,et al.  Comparative protein modeling by satisfaction of spatial restraints. , 1996, Molecular medicine today.

[23]  S. Moro,et al.  Flavonoid derivatives as adenosine receptor antagonists: a comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model. , 1998, Journal of medicinal chemistry.

[24]  Nathan Robertson,et al.  Biophysical Mapping of the Adenosine A2A Receptor , 2011, Journal of medicinal chemistry.

[25]  H. Pajouhesh,et al.  Medicinal chemical properties of successful central nervous system drugs , 2005, NeuroRX.

[26]  J. Shryock,et al.  Synthesis and biological effects of novel 2-amino-3-naphthoylthiophenes as allosteric enhancers of the A1 adenosine receptor. , 2003, Journal of medicinal chemistry.

[27]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[28]  Hege S. Beard,et al.  Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. , 2004, Journal of medicinal chemistry.

[29]  A. Lawrence,et al.  Antagonists of the human adenosine A2A receptor. Part 1: Discovery and synthesis of thieno[3,2-d]pyrimidine-4-methanone derivatives. , 2008, Bioorganic & medicinal chemistry letters.

[30]  Gebhard F. X. Schertler,et al.  Structure of a β1-adrenergic G-protein-coupled receptor , 2008, Nature.

[31]  R. Gillespie,et al.  Antagonists of the human adenosine A2A receptor. Part 3: Design and synthesis of pyrazolo[3,4-d]pyrimidines, pyrrolo[2,3-d]pyrimidines and 6-arylpurines. , 2008, Bioorganic & medicinal chemistry letters.

[32]  Jonathan S. Mason,et al.  Discovery of 1,2,4-Triazine Derivatives as Adenosine A2A Antagonists using Structure Based Drug Design , 2012, Journal of medicinal chemistry.

[33]  Brian K. Shoichet,et al.  Structure-Based Discovery of A2A Adenosine Receptor Ligands , 2010, Journal of medicinal chemistry.

[34]  J. Daly,et al.  1,3-Dialkyl-8-(p-sulfophenyl)xanthines: potent water-soluble antagonists for A1- and A2-adenosine receptors. , 1985, Journal of medicinal chemistry.