Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃ Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary.

ABSTRACT: Distinguishing compounds' agonistic or antagonistic behavior would be of great utility for the rational discovery of selective modulators. We synthesized truncated nucleoside derivatives and discovered 6c (K_i = 2.40 nM) as a potent human A₃ adenosine receptor (hA₃AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA₃AR homology models that consider the pharmacological profiles of the ligands. Taken together with molecular dynamics (MD) simulation and three-dimensional (3D) structural network analysis of the receptor-ligand complex, the results indicated that the hydrogen bonding with Thr94^3.36 and His272^7.43 could make a st

SUBMITTER: Lee Y 

PROVIDER: S-EPMC8840841 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature