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Exploring the Inhibitory Potential of Xanthohumol on Mek1/2: A Molecular Docking and Dynamics Simulation Investigation Publisher



Siahmazgi ZG1 ; Irani S2 ; Ghiaseddin A3 ; Soutodeh F4 ; Gohari Z4 ; Afifeh J1 ; Pashapouryeganeh A1 ; Samimi H1 ; Naderi M5 ; Fallah P6 ; Haghpanah V1, 7
Authors
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Authors Affiliations
  1. 1. Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
  3. 3. Department of Biomedical Engineering Division, Chemical Engineering Faculty, Tarbiat Modares University, Tehran, Iran
  4. 4. Department of Molecular Biology and Genetic Engineering, Stem Cell Technology Research Center, Tehran, Iran
  5. 5. Digestive Diseases Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Laboratory Science Department, Allied Medicine Faculty, Alborz University of Medical Sciences, Karaj, Iran
  7. 7. Personalized Medicine Research Center, Endocrinology and Metabolism Clinical Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran

Source: Research in Pharmaceutical Sciences Published:2024


Abstract

Background and purpose: Xanthohumol (Xn), a small molecule found in Humulus lupulus, has shown promise as an anti-cancer compound. This in silico study was performed to understand the mechanism of action of Xn as a natural compound on MEK1/2 by simulation. Experimental approach: After ligand and protein preparation, the best binding energy was determined using Autodock 4.2. Additionally, molecular dynamics simulations of the MEK1/2-Xn and BRaf-MEK1/2-Xn complexes were conducted using GROMACS 2022.1 software and compared to the complexes of MEK1/2-trametinib (Tra) and BRaf-MEK1/2-Tra. Findings/Results: The docking results revealed that the best binding energies for MEK1-Xn (-10.70 Kcal/mol), MEK2-Xn (-9.41 Kcal/mol), BRaf-MEK1-Xn (-10.91 Kcal/mol), and BRaf-MEK2-Xn (-8.54 Kcal/mol) were very close to those of the Tra complexes with their targets, MEK1 and MEK2. Furthermore, Xn was found to interact with serine 222 at the active site of these two kinases. The results of the molecular dynamics simulations also indicated that Xn induced changes in the secondary structure of the studied proteins. The root mean square of proteins and the mean radius of gyration showed significant fluctuations. Conclusion and implications: The findings of the study suggested that Xn, as a novel bioactive compound, potentially inhibits the MEK1/2 function in cancer cells. © 2024 Research in Pharmaceutical Sciences.
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