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Updated: Jan 4, 2026
Incorporating Target Protein Structure Flexibility and Dynamics in Computational Drug Discovery Using Ensemble-Based Docking Analysis
Published on: June 20, 2025
Clustering and Sampling of the c-Met Conformational Space: A Computational Drug Discovery Study
Korosh Mashayekh1, Shahrzad Sharifi1, Tahereh Damghani1,2
1Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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.
