Title:Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study
Volume: 22
Issue: 9
Author(s): Korosh Mashayekh, Shahrzad Sharifi, Tahereh Damghani, Maryam Elyasi, Mohammad S. Avestan and Somayeh Pirhadi*
Affiliation:
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz,Iran
Keywords:
c-Met, molecular dynamics simulation, docking, virtual screening, clustering, potent inhibitor.
Abstract:
Background: c-Met kinase plays a critical role in a myriad of human cancers, and a
massive scientific work was devoted to design more potent inhibitors.
Objective: In this study, 16 molecular dynamics simulations of different complexes of potent c-Met
inhibitors with U-shaped binding mode were carried out regarding the dynamic ensembles to
design novel potent inhibitors.
Methods: A cluster analysis was performed, and the most representative frame of each complex
was subjected to the structure-based pharmacophore screening. The GOLD docking program
investigated the interaction energy and pattern of output hits from the virtual screening. The most
promising hits with the highest scoring values that showed critical interactions with c-Met were
presented for ADME/Tox analysis.
Results: The screening yielded 45,324 hits that all of them were subjected to the docking studies
and 10 of them with the highest-scoring values having diverse structures were presented for
ADME/Tox analyses.
Conclusion: The results indicated that all the hits shared critical Pi-Pi stacked and hydrogen bond
interactions with Tyr1230 and Met1160 respectively.
