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Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPAR? Antagonists with Anti-adipogenic Effects.

ABSTRACT: Conformational change in helix 12 can alter ligand-induced PPAR? activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPAR? antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPAR?. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPAR?. Additionally, biological assays showed that this new series of PPAR? antagonists more strongly inhibit adipocyte differentiation and PPAR?2-induced transcriptional activity than GW9662.

SUBMITTER: Jin Y

PROVIDER: S-EPMC5046141 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Discovery of Isoquinolinoquinazolinones as a Novel Class of Potent PPARγ Antagonists with Anti-adipogenic Effects.

Jin Yifeng Y Han Younho Y Khadka Daulat Bikram DB Zhao Chao C Lee Kwang Youl KY Cho Won-Jea WJ

Scientific reports 20161003

Conformational change in helix 12 can alter ligand-induced PPARγ activity; based on this reason, isoquinolinoquinazolinones, structural homologs of berberine, were designed and synthesized as PPARγ antagonists. Computational docking and mutational study indicated that isoquinolinoquinazolinones form hydrogen bonds with the Cys285 and Arg288 residues of PPARγ. Furthermore, SPR results demonstrated strong binding affinity of isoquinolinoquinazolinones towards PPARγ. Additionally, biological assays ...[more]

PMID: 27695006

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