罗格列酮
过氧化物酶体增殖物激活受体
药理学
过剩4
脂肪生成
计算生物学
虚拟筛选
化学
作用机理
对接(动物)
受体
生物
生物化学
药物发现
体外
医学
基因
染色体易位
护理部
作者
Fangyuan Chen,Lei Ma,Guihui Cai,Junyuan Tang,Yi Wang,Qingmei Liu,Xiawen Liu,Ning Hou,Zhi Zhou,Wei Yi
标识
DOI:10.1016/j.biopha.2022.113653
摘要
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.
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