Abstract
Objectives
Mitogen-activated protein kinase-3 (MAPK3) is the upstream regulator in the MAPK cascade and is involved in many critical signaling pathways and biological processes, such as cell proliferation, survival, and apoptosis. MAPK3 overexpression is linked to onset, development, metastasis, and drug resistance in several human cancers. Thus, identifying novel and effective MAPK3 inhibitors is highly demanded. Herein, we aimed to discover organic compounds from cinnamic acid derivatives as potential MAPK3 inhibitors.
Methods
The binding affinity of 20 cinnamic acids to the MAPK3 active site was tested using the AutoDock 4.0 software. Top-ranked cinnamic acids were ranked based on the ΔG binding values between the ligands and the receptor’s active site. Interaction modes between top-ranked cinnamic acids and MAPK3 catalytic site were indicated using the Discovery Studio Visualizer tool. Molecular dynamics (MD) simulation was carried out to study the stability of the docked pose for the most potent MAPK3 inhibitor in this study.
Results
Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate exhibited a salient binding affinity to the MAPK3 active site with the criteria of ΔG binding <−10 k cal/mol. Further, the inhibition constant value for cynarin was calculated at the picomolar concentration. The docked pose of cynarin within the MAPK3 catalytic domain was stable in 100 ns simulation.
Conclusions
Cynarin, chlorogenic acid, rosmarinic acid, caffeic acid 3-glucoside, and cinnamyl caffeate might be helpful in cancer therapy by inhibiting MAPK3.
Acknowledgments
The authors would like to thank the Research Center for Molecular Medicine, Dental Research Center, Hamadan University of Medical Sciences, Hamadan, Iran, for their support.
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Research funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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Author contributions: AT, and ZB designed the study. Docking operations were conducted by AiT. MD simulations were performed by AT. The results were analyzed and discussed by AT and ZB. AT wrote the manuscript. ZB edited the manuscript. All authors read and approved the final version of the manuscript.
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Conflict of interests: The authors declare that they have no competing interests.
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Ethical approval: The present study was approved by the Ethics Committee of Hamadan University of Medical Sciences, Hamadan, Iran (ethics no. IR.UMSHA.REC.1401.252).
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Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.
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