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Derivation of Self-inhibitory Helical Peptides to Target Rho-kinase Dimerization in Cerebrovascular Malformation: Structural Bioinformatics Analysis and Peptide Binding Assay.
Wang, Xuyang; Hou, Dianqi; Dai, Weiwei; Gao, Wenwei; Ju, Shiming; Cao, Heli; Zhang, Lin; Wang, Gan; Guo, Yan; Chen, Shiwen; Tian, Hengli; Li, Zhiqiang.
Affiliation
  • Wang X; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Hou D; Department of Neurosurgery, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, 200080, China.
  • Dai W; The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • Gao W; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Ju S; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Cao H; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Zhang L; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Wang G; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Guo Y; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Chen S; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China.
  • Tian H; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital, Shanghai, 200233, China. tianhengli@126.com, tianhengli1964@yahoo.com.cn.
  • Li Z; Department of Neurosurgery, Shanghai Jiao Tong University Affiliated 6th People's Hospital South Campus, Shanghai, 201400, China. lzq_999@163.com.
Mol Inform ; 35(6-7): 262-7, 2016 07.
Article in En | MEDLINE | ID: mdl-27492240
Rho-kinase dimerization is essential for its kinase activity and biological function; disruption of the dimerization has recently been established as a new and promising therapeutics strategy for cerebrovascular malformation (CM). Based on Rho-kinase dimer crystal structure we herein combined in silico analysis and in vitro assay to rationally derive self-inhibitory peptides from the dimerization interface. Three peptides namely Hlp1, Hlp2 and Hlp3 were successfully designed that have potential capability to rebind at the dimerization domain of Rho-kinase. Molecular dynamics (MD) simulations revealed that these peptides are helically structured when bound to Rho-kinase, but exhibit partially intrinsic disorder in unbound state. Binding free energy (BFE) analysis suggested that the peptides have a satisfactory energetic profile to interact with Rho-kinase. The computational findings were then substantiated by fluorescence anisotropy assays, conforming that the helical peptides can bind tightly to Rho-kinase with affinity KD at micromolar level. These designed peptides are considered as lead molecular entities that can be further modified and optimized to obtain more potent peptidomimetics as self-competitors to disrupt Rho-kinase dimerization in CM.
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Full text: 1 Database: MEDLINE Main subject: Protein Kinase Inhibitors / Rho-Associated Kinases Language: En Journal: Mol Inform Year: 2016 Type: Article Affiliation country: China

Full text: 1 Database: MEDLINE Main subject: Protein Kinase Inhibitors / Rho-Associated Kinases Language: En Journal: Mol Inform Year: 2016 Type: Article Affiliation country: China