Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ

Seungchan An; Jinha Yu; Hongseok Choi; Hyejin Ko; Sungjin Ahn; Jeayoung C Shin; Jeong Joo Pyo; Lak Shin Jeong; Minsoo Noh

doi:10.1016/j.bmc.2019.115226

Selenium bioisosteric replacement of adenosine derivatives promoting adiponectin secretion increases the binding affinity to peroxisome proliferator-activated receptor δ

Bioorg Med Chem. 2020 Jan 1;28(1):115226. doi: 10.1016/j.bmc.2019.115226. Epub 2019 Nov 28.

Authors

Seungchan An¹, Jinha Yu², Hongseok Choi², Hyejin Ko¹, Sungjin Ahn¹, Jeayoung C Shin¹, Jeong Joo Pyo¹, Lak Shin Jeong³, Minsoo Noh⁴

Affiliations

¹ College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
² College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Pharmaceutical Research Institute, Seoul National University, Seoul 08826, Republic of Korea.
³ College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Pharmaceutical Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: lakjeong@snu.ac.kr.
⁴ College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Natural Products Research Institute, Seoul National University, Seoul 08826, Republic of Korea. Electronic address: minsoonoh@snu.ac.kr.

PMID: 31806266
DOI: 10.1016/j.bmc.2019.115226

Abstract

N⁶-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (1a, IB-MECA) exhibited polypharmacological characteristics targeting A₃ adenosine receptor (AR), peroxisome proliferator-activated receptor (PPAR) γ, and PPARδ, simultaneously. The bioisosteric replacement of oxygen in 4'-oxoadenosines with selenium significantly increased the PPARδ-binding activity. 2-Chloro-N⁶-(3-iodobenzyl)-4'-selenoadenosine-5'-N-methyluronamide (3e) and related 4'-selenoadenosine derivatives significantly enhanced adiponectin biosynthesis during adipogenesis in human bone marrow mesenchymal stem cells (hBM-MSCs). The PPARδ-binding affinity, but not the A₃ AR binding affinity, of 4'-selenoadenosine derivatives correlated with their adiponectin secretion stimulation. Compared with the sugar ring of 4'-oxoadenosine, that of 4'-selenoadenosine was more favorable in forming the South sugar conformation. In the molecular docking simulation, the South sugar conformation of compound 3e formed additional hydrogen bonds inside the PPARδ ligand-binding pocket compared with the North conformation. Therefore, the sugar conformation of 4'-selenoadenosine PPAR modulators affects the ligand binding affinity against PPARδ.

Keywords: Adeonsine A(3) receptor; Adiponectin; PPARγ; PPARδ; Polypharmacology; Selenoadenosine.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives
Adenosine / chemistry
Adenosine / pharmacology*
Adiponectin / biosynthesis*
Cells, Cultured
Dose-Response Relationship, Drug
Humans
Mesenchymal Stem Cells / drug effects
Mesenchymal Stem Cells / metabolism
Molecular Docking Simulation
Molecular Structure
PPAR delta / metabolism*
Selenium / chemistry
Selenium / pharmacology*
Structure-Activity Relationship

Substances

Adiponectin
PPAR delta
Selenium
Adenosine