TY - JOUR
T1 - Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist
T2 - New A3Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary
AU - Lee, Yoonji
AU - Hou, Xiyan
AU - Lee, Jin Hee
AU - Nayak, Akshata
AU - Alexander, Varughese
AU - Sharma, Pankaz K.
AU - Chang, Hyerim
AU - Phan, Khai
AU - Gao, Zhan Guo
AU - Jacobson, Kenneth A.
AU - Choi, Sun
AU - Jeong, Lak Shin
N1 - Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.
PY - 2021/9/9
Y1 - 2021/9/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85114629980&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.1c00239
DO - 10.1021/acs.jmedchem.1c00239
M3 - Article
C2 - 34435786
AN - SCOPUS:85114629980
SN - 0022-2623
VL - 64
SP - 12525
EP - 12536
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 17
ER -