体内
体外
化学
细胞生物学
虚拟筛选
生物化学
生物物理学
计算生物学
生物
药物发现
遗传学
作者
Jianda Yue,Jiawei Xu,Yuelan Yin,Yongqian Shu,Yaqi Li,Tingting Li,Zhimin Zou,Zihan Wang,Fengjiao Li,MengQi Zhang,Songping Liang,Xiao He,Liu Z,Ying Wang
标识
DOI:10.1016/j.ijbiomac.2024.129970
摘要
In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1–4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders. In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2. Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.
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