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
- 주제(기타) Chemistry, Medicinal
- 설명문(일반) [Lee, Yoonji; Lee, Jin Hee; Sharma, Pankaz K.; Chang, Hyerim; Choi, Sun] Ewha Womans Univ, Coll Pharm, Global AI Drug Discovery Ctr, Seoul 03760, South Korea; [Lee, Yoonji; Lee, Jin Hee; Sharma, Pankaz K.; Chang, Hyerim; Choi, Sun] Ewha Womans Univ, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Lee, Yoonji] Chung Ang Univ, Coll Pharm, Seoul 06974, South Korea; [Hou, Xiyan; Nayak, Akshata; Alexander, Varughese; Jeong, Lak Shin] Seoul Natl Univ, Coll Pharm, Seoul 08826, South Korea; [Hou, Xiyan] Dalian Minzu Univ, Coll Life Sci, Dalian 116600, Peoples R China; [Lee, Jin Hee] Ildong Pharmaceut Co Ltd, Res Lab, Hwaseong 18449, South Korea; [Sharma, Pankaz K.] Cotton Univ, Dept Chem, Panbazar 781001, Guwahati, India; [Phan, Khai; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA
- 등재 SCIE, SCOPUS
- OA유형 Green Accepted
- 발행기관 AMER CHEMICAL SOC
- 발행년도 2021
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000183547
- 본문언어 영어
- Published As http://dx.doi.org/10.1021/acs.jmedchem.1c00239
- PubMed https://pubmed.ncbi.nlm.nih.gov/34435786
초록/요약
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.
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