Ligand and Residue Free Energy Perturbations Solve the Dual Binding Mode Proposal for an A_2BAR Partial Agonist.

ABSTRACT: Adenosine receptors, particularly A_2BAR, are gaining attention for their role in pathological conditions such as cancer immunotherapy, prompting the exploration for promising therapeutic applications. Despite numerous selective A_2BAR antagonists, the lack of selective full agonists makes the partial agonist BAY60-6583 one of the most interesting activators of this receptor. Recent cryo-EM structures have univocally revealed the binding mode of nonselective ribosidic agonists such as adenosine and its derivative NECA to A_2BAR; however, two independent structures with BAY60-6583 show alternative binding orientations, raising the question of which is the physiologically relevant binding mode. In situations such as this, computational simulations that accuratel

SUBMITTER: Tandaric T 

PROVIDER: S-EPMC11770768 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature