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Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A(3) Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary

Title
Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A(3) Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary
Authors
Lee, YoonjiHou, XiyanLee, Jin HeeNayak, AkshataAlexander, VarugheseSharma, Pankaz K.Chang, HyerimPhan, KhaiGao, Zhan-GuoJacobson, Kenneth A.Choi, SunJeong, Lak Shin
Ewha Authors
최선Pankaz Kumar Sharma이윤지
SCOPUS Author ID
최선scopus; Pankaz Kumar Sharmascopus; 이윤지scopus
Issue Date
2021
Journal Title
JOURNAL OF MEDICINAL CHEMISTRY
ISSN
0022-2623JCR Link

1520-4804JCR Link
Citation
JOURNAL OF MEDICINAL CHEMISTRY vol. 64, no. 17, pp. 12525 - 12536
Publisher
AMER CHEMICAL SOC
Indexed
SCIE; SCOPUS WOS scopus
Document Type
Article
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 (hA(3)AR) agonist, and subtle chemical modification induced a shift from antagonist to agonist. We elucidated this shift by developing new hA(3)AR 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 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.
DOI
10.1021/acs.jmedchem.1c00239
Appears in Collections:
약학대학 > 약학과 > Journal papers
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