Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A3Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary

Yoonji Lee; Xiyan Hou; Jin Hee Lee; Akshata Nayak; Varughese Alexander; Pankaz K. Sharma; Hyerim Chang; Khai Phan; Zhan Guo Gao; Kenneth A. Jacobson; Sun Choi; Lak Shin Jeong

doi:10.1021/acs.jmedchem.1c00239

Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary

Yoonji Lee, Xiyan Hou, Jin Hee Lee, Akshata Nayak, Varughese Alexander, Pankaz K. Sharma, Hyerim Chang, Khai Phan, Zhan Guo Gao, Kenneth A. Jacobson, Sun Choi, Lak Shin Jeong

Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

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.

Original language	English
Pages (from-to)	12525-12536
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	17
DOIs	https://doi.org/10.1021/acs.jmedchem.1c00239
State	Published - 9 Sep 2021

Bibliographical note

Funding 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).

Publisher Copyright:
© 2021 The Authors. Published by American Chemical Society.

Access to Document

10.1021/acs.jmedchem.1c00239

Cite this

Lee, Y., Hou, X., Lee, J. H., Nayak, A., Alexander, V., Sharma, P. K., Chang, H., Phan, K., Gao, Z. G., Jacobson, K. A., Choi, S., & Jeong, L. S. (2021). Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary. Journal of Medicinal Chemistry, 64(17), 12525-12536. https://doi.org/10.1021/acs.jmedchem.1c00239

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title = "Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A3Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary",

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.",

author = "Yoonji Lee and Xiyan Hou and Lee, {Jin Hee} and Akshata Nayak and Varughese Alexander and Sharma, {Pankaz K.} and Hyerim Chang and Khai Phan and Gao, {Zhan Guo} and Jacobson, {Kenneth A.} and Sun Choi and Jeong, {Lak Shin}",

note = "Funding 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). Publisher Copyright: {\textcopyright} 2021 The Authors. Published by American Chemical Society.",

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Lee, Y, Hou, X, Lee, JH, Nayak, A, Alexander, V, Sharma, PK, Chang, H, Phan, K, Gao, ZG, Jacobson, KA, Choi, S & Jeong, LS 2021, 'Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary', Journal of Medicinal Chemistry, vol. 64, no. 17, pp. 12525-12536. https://doi.org/10.1021/acs.jmedchem.1c00239

Subtle Chemical Changes Cross the Boundary between Agonist and Antagonist: New A₃Adenosine Receptor Homology Models and Structural Network Analysis Can Predict This Boundary. / Lee, Yoonji; Hou, Xiyan; Lee, Jin Hee et al.
In: Journal of Medicinal Chemistry, Vol. 64, No. 17, 09.09.2021, p. 12525-12536.

Research output: Contribution to journal › Article › peer-review

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AU - Gao, Zhan Guo

AU - Jacobson, Kenneth A.

AU - Choi, Sun

AU - Jeong, Lak Shin

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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.

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