Crystal Structure and Subsequent Ligand Design of a Nonriboside Partial Agonist Bound to the Adenosine A 2A Receptor.

Autor:	Amelia T; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.; School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, 40132 Bandung, Indonesia., van Veldhoven JPD; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., Falsini M; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., Liu R; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., Heitman LH; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., van Westen GJP; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., Segala E; Sosei Heptares, Steinmetz Building, Granta Park, Cambridge CB21 6DG, United Kingdom., Verdon G; Sosei Heptares, Steinmetz Building, Granta Park, Cambridge CB21 6DG, United Kingdom., Cheng RKY; Sosei Heptares, Steinmetz Building, Granta Park, Cambridge CB21 6DG, United Kingdom., Cooke RM; Sosei Heptares, Steinmetz Building, Granta Park, Cambridge CB21 6DG, United Kingdom., van der Es D; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands., IJzerman AP; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2021 Apr 08; Vol. 64 (7), pp. 3827-3842. Date of Electronic Publication: 2021 Mar 25.
DOI:	10.1021/acs.jmedchem.0c01856
Abstrakt:	In this study, we determined the crystal structure of an engineered human adenosine A 2A receptor bound to a partial agonist and compared it to structures cocrystallized with either a full agonist or an antagonist/inverse agonist. The interaction between the partial agonist, belonging to a class of dicyanopyridines, and amino acids in the ligand binding pocket inspired us to develop a small library of derivatives and assess their affinity in radioligand binding studies and potency and intrinsic activity in a functional, label-free, intact cell assay. It appeared that some of the derivatives retained the partial agonist profile, whereas other ligands turned into inverse agonists. We rationalized this remarkable behavior with additional computational docking studies.
Databáze:	MEDLINE
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