title: Stepwise high-throughput virtual screening of Rho kinase inhibitors from natural product library and potential therapeutics for pulmonary hypertension.
abstract: BACKGROUND
  Pulmonary hypertension (PH) is a devastating disease characterized by progressive elevation of pulmonary arterial pressure and vascular resistance due to pulmonary vasoconstriction and vessel remodeling. The activation of RhoA/Rho-kinase (ROCK) pathway plays a central role in the pathologic progression of PH and thus the Rho kinase, an essential effector of the ROCK pathway, is considered as a potential therapeutic target to attenuate PH.
  
  
  OBJECTIVE
  In the current study, a synthetic pipeline is used to discover new potent Rho inhibitors from various natural products.
  
  
  METHODS
  In the pipeline, the stepwise high-throughput virtual screening, quantitative structure-activity relationship (QSAR)-based rescoring, and kinase assay were integrated. The screening was performed against a structurally diverse, drug-like natural product library, from which six identified compounds were tested to determine their inhibitory potencies agonist Rho by using a standard kinase assay protocol.
  
  
  RESULTS
  With this scheme, we successfully identified two potent Rho inhibitors, namely phloretin and baicalein, with activity values of IC50 = 0.22 and 0.95 μM, respectively.
  
  
  CONCLUSIONS
  Structural examination suggested that complicated networks of non-bonded interactions such as hydrogen bonding, hydrophobic forces, and van der Waals contacts across the complex interfaces of Rho kinase are formed with the screened compounds.
authors: Department of Cardiology, Anhui Provincial Hospital , Hefei , China.
authors: Hao
authors: H
authors: Su
authors: Ji
authors: J
authors: Yan
authors: Jian
authors: J
authors: Xu
authors: Xi-Zhen
authors: XZ
authors: Fan
authors: Xian-Lin
authors: XL
authors: Sun
authors: Kang-Yu
authors: KY
authors: Chen
mesh_terms: D001688:Biological Products / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015723:Gene Library; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D021281:Quantitative Structure-Activity Relationship; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D001688:Biological Products; D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases
keywords: Inhibitor; Rho kinase; natural product; pulmonary hypertension