PUBLICATION

Discovery of Rho-kinase inhibitors by docking-based virtual screening

Authors
Shen, M., Yu, H., Li, Y., Li, P., Pan, P., Zhou, S., Zhang, L., Li, S., Lee, S.M., and Hou, T.
ID
ZDB-PUB-130412-19
Date
2013
Source
Molecular Biosystems   9(6): 1511-21 (Journal)
Registered Authors
Keywords
none
MeSH Terms
  • Animals
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/metabolism
  • Antineoplastic Agents/pharmacology*
  • Atorvastatin
  • Breast Neoplasms/drug therapy
  • Breast Neoplasms/metabolism
  • Cell Line, Tumor
  • Cerebral Hemorrhage/chemically induced
  • Cerebral Hemorrhage/drug therapy
  • Drug Evaluation, Preclinical*
  • Drug Screening Assays, Antitumor*
  • Female
  • HeLa Cells
  • Heptanoic Acids/pharmacology
  • Humans
  • Lung Neoplasms/drug therapy
  • Lung Neoplasms/metabolism
  • Models, Molecular
  • Molecular Docking Simulation*
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Multiple Myeloma/drug therapy
  • Multiple Myeloma/metabolism
  • Protein Kinase Inhibitors/chemistry
  • Protein Kinase Inhibitors/metabolism
  • Protein Kinase Inhibitors/pharmacology*
  • Pyrroles/pharmacology
  • Zebrafish
  • rho-Associated Kinases/antagonists & inhibitors*
  • rho-Associated Kinases/metabolism
PubMed
23549429 Full text @ Mol. Biosyst.
Abstract

Rho kinases (ROCK1 and ROCK2) belong to serine/threonine (Ser/Thr) protein kinase family, and play the central roles in the organization of the actin cytoskeleton. Therefore, Rho kinases have become attractive targets for the treatments of many diseases, such as cancer, renal disease, hypertension, ischemia, and stroke. In order to develop small-molecule inhibitors of ROCK1, molecular docking was utilized to virtually screen two chemical databases and identify molecules that interact with ROCK1. A small set of virtual hits was purchased and submitted to a series of experimental assays. The in vitro enzyme-based and cell-based assays reveal that 12 compounds have good inhibitory activity against ROCK1 in the micro molar regime (IC50 values between about 7 and 28 μM) and antitumor activity against lung cancer, breast cancer or/and myeloma cell lines. The structural analysis shows that two active compounds present novel scaffolds and are potential leads for the development of novel anti-cancer drugs. We then characterized the interaction patterns between ROCK1 and two inhibitors with novel scaffolds by molecular dynamics (MD) simulations and free energy decomposition analysis. In addition, the pharmacological effect of the two ROCK1 inhibitors with novel scaffolds on atorvastatin-induced cerebral hemorrhage was evaluated by using zebrafish model, and one compound candidate is able to prevent atorvastatin-induced cerebral hemorrhage effectively.

Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping