Structural basis of valmerins as dual inhibitors of GSK3β/CDK5

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• 作者：Xiaolong Li (1)
  Xiaowei Wang (2)
  Zibin Tian (2)
  Houling Zhao (1)
  Da Liang (1)
  Weisong Li (1)
  Yujin Qiu (1)
  Shaoyong Lu (3)
  
• 关键词：GSK3β/CDK5 ; MD simulation ; Molecular docking ; MM ; PBSA ; PCA
• 刊名：Journal of Molecular Modeling
• 出版年：2014
• 出版时间：September 2014
• 年：2014
• 卷：20
• 期：9
• 全文大小：2,522 KB
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• 作者单位：Xiaolong Li (1)
  Xiaowei Wang (2)
  Zibin Tian (2)
  Houling Zhao (1)
  Da Liang (1)
  Weisong Li (1)
  Yujin Qiu (1)
  Shaoyong Lu (3)
  
  1. Depatment of Spinal Surgery, Affiliated Hospital of Weifang Medical University, Weifang, 261000, China
  2. Department of Gastroenterology, Affiliated Hospital of Medical College, Qingdao University, Qingdao, 266003, China
  3. Medicinal Bioinformatics Center, School of Medicine, Shanghai JiaoTong University, Shanghai, 200025, China
  
• ISSN：0948-5023

文摘

Development of multi-target drugs is becoming increasingly attractive in the repertoire of protein kinase inhibitors discovery. In this study, we carried out molecular docking, molecular dynamics simulations, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations, principal component analysis (PCA), and dynamical cross-correlation matrices (DCCM) to dissect the molecular mechanism for the valmerin-19 acting as a dual inhibitor for glycogen synthase kinase 3β (GSK3β) and cyclin-dependent kinase 5 (CDK5). Detailed MM-PBSA calculations revealed that the binding free energies of the valmerin-19 to GSK3β/CDK5 were calculated to be ?2.60?±-.28?kcal mol-1 and ?1.85?±-.54?kcal mol-1, respectively, indicating that valmerin-19 has the potential to act as a dual inhibitor of GSK3β/CDK5. The analyses of PCA and DCCM results unraveled that binding of the valmerin-19 reduced the conformational dynamics of GSK3β/CDK5 and the valmerin-19 bound to GSK3β/CDK5 might occur mostly through a conformational selection mechanism. This study may be helpful for the future design of novel and potent dual GSK3β/CDK5 inhibitors.