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

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

  • J Med Chem. 2021 Sep 9;64(17):12525-12536. doi: 10.1021/acs.jmedchem.1c00239.
Yoonji Lee 1 2,  Xiyan Hou 3 4,  Jin Hee Lee 1,  Akshata Nayak 3,  Varughese Alexander 3,  Pankaz K Sharma 1,  Hyerim Chang 1,  Khai Phan 5,  Zhan-Guo Gao 5,  Kenneth A Jacobson 5,  Sun Choi 1,  Lak Shin Jeong 3
Affiliations

Affiliations

  • 1 Global AI Drug Discovery Center, College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Republic of Korea.
  • 2 College of Pharmacy, Chung-Ang University, Seoul 06974, Republic of Korea.
  • 3 College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
  • 4 College of Life Science, Dalian Minzu University, Dalian 116600, People's Republic of China.
  • 5 Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland 20892, United States.
PMID: 34435786 DOI: 10.1021/acs.jmedchem.1c00239
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 (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.

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