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Structure-based discovery of novel chemotypes for adenosine A(2A) receptor antagonists

Academic Article
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Overview

authors

  • Katritch, Vsevolod
  • Jaakola, V. P.
  • Lane, J. R.
  • Lin, J.
  • Ijzerman, A. P.
  • Yeager, Mark
  • Kufareva, I.
  • Stevens, Raymond
  • Abagyan, R.

publication date

  • February 2010

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The recent progress in crystallography of G-protein coupled receptors opens an unprecedented venue for structure-based GPCR drug discovery. To test efficiency of the structure-based approach, we performed molecular docking and virtual ligand screening (VLS) of more than 4 million commercially available "drug-like" and ''lead-like'' compounds against the A(2A)AR 2.6 A resolution crystal structure. Out of 56 high ranking compounds tested in A(2A)AR binding assays, 23 showed affinities under 10 microM, 11 of those had sub-microM affinities and two compounds had affinities under 60 nM. The identified hits represent at least 9 different chemical scaffolds and are characterized by very high ligand efficiency (0.3-0.5 kcal/mol per heavy atom). Significant A(2A)AR antagonist activities were confirmed for 10 out of 13 ligands tested in functional assays. High success rate, novelty, and diversity of the chemical scaffolds and strong ligand efficiency of the A(2A)AR antagonists identified in this study suggest practical applicability of receptor-based VLS in GPCR drug discovery.

subject areas

  • Adenosine A2 Receptor Antagonists
  • Animals
  • Anthraquinones
  • Cell Line
  • Cell Membrane
  • Cyclic AMP
  • Databases, Factual
  • Humans
  • Insecta
  • Isoindoles
  • Libraries, Digital
  • Ligands
  • Models, Molecular
  • Naphthalenes
  • Protein Conformation
  • Pyridines
  • Radioligand Assay
  • Receptor, Adenosine A2A
  • Structure-Activity Relationship
  • Triazines
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Identity

PubMed Central ID

  • PMC2826142

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm901647p

PubMed ID

  • 20095623
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Additional Document Info

start page

  • 1799

end page

  • 1809

volume

  • 53

issue

  • 4

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