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Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study

Author(s):

Korosh Mashayekh, Shahrzad Sharifi, Tahereh Damghani, Maryam Elyasi, Mohammad Sadegh Avestan and Somayeh Pirhadi*   Pages 1 - 15 ( 15 )

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 research 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 interaction energy and pattern of output hits from the virtual screening was investigated by the GOLD docking program. 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 share critical Pi-Pi stacked and hydrogen bond interactions with Tyr1230 and Met1160 respectively.

Keywords:

c-Met, Molecular dynamics simulation, Docking, Virtual screening, Clustering

Affiliation:

Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Department of Chemistry, University of Cincinnati, Cincinnati, Ohio 45221, Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz



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