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Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists

Katritch, Vsevolod; Jaakola, Veli-Pekka; Lane, J Robert; Lin, Judy; Ijzerman, Adriaan P; Yeager, Mark; Kufareva, Irina; Stevens, Raymond C; Abagyan, Ruben


Vsevolod Katritch

Veli-Pekka Jaakola

Associate Professor

Judy Lin

Adriaan P Ijzerman

Mark Yeager

Irina Kufareva

Raymond C Stevens

Ruben Abagyan


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.


Katritch, V., Jaakola, V., Lane, J. R., Lin, J., Ijzerman, A. P., Yeager, M., …Abagyan, R. (2010). Structure-Based Discovery of Novel Chemotypes for Adenosine A2A Receptor Antagonists. Journal of Medicinal Chemistry, 53(4), 1799-1809.

Journal Article Type Article
Acceptance Date Jan 22, 2010
Publication Date Feb 25, 2010
Deposit Date Apr 22, 2020
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 53
Issue 4
Pages 1799-1809
Public URL
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