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 (Ki = 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 Thr943.36 and His2727.43 could make a stable interaction between the 3'-amino group with TM3 and TM7, and the corresponding induced-fit effects may play important roles in rendering the agonistic effect. Our results provide a more precise understanding of the compounds' actions at the atomic level and a rationale for the design of new drugs with specific pharmacological profiles.
Bibliographical noteFunding Information:
This work was supported by the Mid-career Researcher Program (NRF-2016R1A2B3010164, NRF-2021R1A2B5B02001544) and the Ministry of Health and Welfare (MOHW) grant (HI20C241800020) to L.S.J., the Mid-career Researcher Program (NRF-2020R1A2C2101636), Medical Research Center (MRC) grant (2018R1A5A2025286), and Bio & Medical Technology Development Program (NRF-2019M3E5D4065251) funded by the Ministry of Science and ICT (MSIT) and the Ministry of Health and Welfare (MOHW) through the National Research Foundation of Korea (NRF) and the Ewha Womans University Research Grant of 2021 to S.C., the General Research Program (2021R1F1A1052149) to Y.L., and NIDDK Intramural Research Program (ZIADK31117).
© 2021 The Authors. Published by American Chemical Society.