Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation

Fangyuan Chen; Lei Ma; Guihui Cai; Junyuan Tang; Yi Wang; Qingmei Liu; Xiawen Liu; Ning Hou; Zhi Zhou; Wei Yi

doi:10.1016/j.biopha.2022.113653

Identification of a novel PPARγ modulator with good anti-diabetic therapeutic index via structure-based screening, optimization and biological validation

Biomed Pharmacother. 2022 Oct:154:113653. doi: 10.1016/j.biopha.2022.113653. Epub 2022 Sep 7.

Authors

Fangyuan Chen¹, Lei Ma¹, Guihui Cai¹, Junyuan Tang¹, Yi Wang¹, Qingmei Liu¹, Xiawen Liu¹, Ning Hou², Zhi Zhou³, Wei Yi⁴

Affiliations

¹ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China.
² Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: houning@gzhmu.edu.cn.
³ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China; The Sixth Affiliated Hospital and Qingyuan People's Hospital, Guangzhou Medical University, Qingyuan, Guangdong 511518, China. Electronic address: zhouzhi@gzhmu.edu.cn.
⁴ Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Degradation & Molecular Target and Clinical Pharmacology, the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. Electronic address: yiwei@gzhmu.edu.cn.

PMID: 36942599
DOI: 10.1016/j.biopha.2022.113653

Abstract

PPARγ is well-known as the target receptor of TZD anti-diabetic drugs. However, recently the therapeutic benefits of these TZD drugs have been compromised by many severe side effects because of their full PPARγ agonistic action to lock the AF-2 helix. Herein, we conducted a virtual screening in the combination with structure-based design, synthesis and biological evaluation both in vitro and in vivo, leading to the identification of a potent candidate YG-C-20 as the SPPARγM with improved and safer anti-diabetic therapeutics. Mechanistically, this compound presented such desired pharmacological profiles (e.g., preferable anti-diabetic efficiencies and minimized side effects) mainly via selectively inhibiting the CDK5-mediated phosphorylation of PPARγ-Ser273 and up-regulating the expression of insulin-sensitive genes Adiponectin and Glut4, yet lacking the classical full agonism to induce the adipogenesis and the expression of key adipogenic genes including PPARγ, aP2, CD36, LPL, C/EBPα and FASN. Further validation led to the final recognition of its (R)-configured isomer as the potential conformational form. Subsequent molecular docking studies revealed a unique hydrogen-bonding network of (R)-YG-C-20 with three full PPARγ agonism-unrelated residues, especially with PPARγ-Ser273 phosphorylation-associated site Ser342, which not only gives a clear verification for our structure-based design but also provides a proof of concept for the abovementioned molecular mechanism.

Keywords: (S)-VSP-77 (PubChem CID: 139267749); 3-Isobutyl-1-methylxanthine (PubChem CID: 3758); Anti-diabetic effects; Benzozodihydropyran derivatives; Decanoic acid (PubChem CID: 2969); Dexamethasone (PubChem CID: 5743); Dimethyl sulfoxide (PubChem CID: 679); Fenticonazole nitrate (PubChem CID: 51754); Glucose (PubChem CID: 5793); Insulin (PubChem CID: 16131098); PPARγ-Ser273 phosphorylation; Pioglitazone (PubChem CID: 4829); Rosiglitazone (PubChem CID: 77999); SB-VHTS; SPPARγM.

MeSH terms

Molecular Docking Simulation
PPAR gamma* / metabolism

Substances

PPAR gamma