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  3. Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments

Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments

  • Int J Biol Macromol. 2024 Feb 6;262(Pt 1):129970. doi: 10.1016/j.ijbiomac.2024.129970.
Jianda Yue 1,  Jiawei Xu 1,  Yekui Yin 1,  Yuanyuan Shu 1,  Yaqi Li 2,  Tingting Li 1,  Zirui Zou 1,  Zihan Wang 1,  Fengjiao Li 1,  Mengqi Zhang 1,  Songping Liang 1,  Xiao He 3,  Zhonghua Liu 4,  Ying Wang 5
Affiliations

Affiliations

  • 1 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China.
  • 2 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China.
  • 3 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, Shanghai Frontiers Science Center of Molecule Intelligent Syntheses, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200062, China; New York University-East China Normal University Center for Computational Chemistry, New York University Shanghai, Shanghai 200062, China.
  • 4 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China. Electronic address: liuzh@hunnu.edu.
  • 5 The National and Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, China; Peptide and Small Molecule Drug R&D Plateform, Furong Laboratory, Hunan Normal University, Changsha 410081, Hunan, China; Institute of Interdisciplinary Studies, Hunan Normal University, Changsha 410081, China. Electronic address: wangyin@hunnu.edu.cn.
PMID: 38325689 DOI: 10.1016/j.ijbiomac.2024.129970
Abstract

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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