Cell Biochemistry and Biophysics

, Volume 76, Issue 1–2, pp 135–145 | Cite as

Identification of Phytochemicals Targeting c-Met Kinase Domain using Consensus Docking and Molecular Dynamics Simulation Studies

  • Shima Aliebrahimi
  • Shideh Montasser KouhsariEmail author
  • Seyed Nasser Ostad
  • Seyed Shahriar Arab
  • Leila Karami
Original Paper


c-Met receptor tyrosine kinase is a proto-oncogene whose aberrant activation is attributed to a lower rate of survival in most cancers. Natural product-derived inhibitors known as “fourth generation inhibitors” constitute more than 60% of anticancer drugs. Furthermore, consensus docking approach has recently been introduced to augment docking accuracy and reduce false positives during a virtual screening. In order to obtain novel small-molecule Met inhibitors, consensus docking approach was performed using Autodock Vina and Autodock 4.2 to virtual screen Naturally Occurring Plant-based Anti-cancer Compound–Activity–Target database against active and inactive conformation of c-Met kinase domain structure. Two hit molecules that were in line with drug-likeness criteria, desired docking score, and binding pose were subjected to molecular dynamics simulations to elucidate intermolecular contacts in protein–ligand complexes. Analysis of molecular dynamics simulations and molecular mechanics Poisson–Boltzmann surface area studies showed that ZINC08234189 is a plausible inhibitor for the active state of c-Met, whereas ZINC03871891 may be more effective toward active c-Met kinase domain compared to the inactive form due to higher binding energy. Our analysis showed that both the hit molecules formed hydrogen bonds with key residues of the hinge region (P1158, M1160) in the active form, which is a hallmark of kinase domain inhibitors. Considering the pivotal role of HGF/c-Met signaling in carcinogenesis, our results propose ZINC08234189 and ZINC03871891 as the therapeutic options to surmount Met-dependent cancers.


Consensus docking c-Met inhibitor Molecular dynamics simulation Binding free energy Natural products 



This research has been supported by Grant Number 93013896 from Iran National Science Foundation (INSF) and 94-01-33-28717 from Deputy of Research, Tehran University of Medical Science.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing interests.


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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Shima Aliebrahimi
    • 1
  • Shideh Montasser Kouhsari
    • 1
    Email author
  • Seyed Nasser Ostad
    • 2
  • Seyed Shahriar Arab
    • 3
  • Leila Karami
    • 4
  1. 1.Department of Cellular and Molecular BiologySchool of Biology, College of Science, University of TehranTehranIran
  2. 2.Department of Toxicology and PharmacologyFaculty of Pharmacy and Poisoning Research Center, Tehran University of Medical SciencesTehranIran
  3. 3.Department of BiophysicsSchool of Biological Sciences, Tarbiat Modares UniversityTehranIran
  4. 4.Department of Cell and Molecular BiologyFaculty of Biological Sciences, Kharazmi UniversityTehranIran

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