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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

Authors

Vsevolod Katritch

Veli-Pekka Jaakola

ROB LANE ROB.LANE@NOTTINGHAM.AC.UK
Associate Professor

Judy Lin

Adriaan P Ijzerman

Mark Yeager

Irina Kufareva

Raymond C Stevens

Ruben Abagyan



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.

Journal Article Type Article
Publication Date Feb 25, 2010
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 53
Issue 4
Pages 1799-1809
APA6 Citation 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. https://doi.org/10.1021/jm901647p
DOI https://doi.org/10.1021/jm901647p
Publisher URL https://pubs.acs.org/doi/10.1021/jm901647p
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