Exploring the inhibitory potential of xanthohumol on MEK1/2: a molecular docking and dynamics simulation investigation

Zohreh Gholizadeh Siahmazgi , Shiva Irani, Ali Ghiaseddin, Fereshteh Soutodeh, Zahra Gohari, Jaber Afifeh, Amirreza Pashapouryeganeh, Hilda Samimi, Mahmood Naderi, Parviz Fallah , Vahid Haghpanah

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.

 

 


Keywords


Active site; MEK1; MEK2; Molecular dynamic simulation; Xanthohumol.

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Akinleye A, Furqan M, Mukhi N, Ravella P, Liu D. MEK and the inhibitors: From bench to bedside. J Hematol Oncol. 2013;6(27):1-11.DOI: 10.1186/1756-8722-6-27.

Ohren JF, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11(12):1192-1197.DOI: 10.1038/nsmb859.

McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EWT, Chang F, et al. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 2007;1773(8):1263-1284.

DOI: 10.1016/j.bbamcr.2006.10.001.

Wright CJM, McCormack PL. Trametinib: first global approval. Drugs. 2013;73(11):1245-1254.DOI: 10.1007/s40265-013-0096-1.

Patel M, Eckburg A, Gantiwala S, Hart Z, Dein J, Lam K, et al. Resistance to molecularly targeted therapies in melanoma. Cancers (Basel). 2021;13(5):1-25.DOI: 10.3390/cancers13051115.

Caunt CJ, Sale MJ, Smith PD, Cook SJ. MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nat Rev Cancer. 2015;15(10):577-592.DOI: 10.1038/nrc4000.

Cheng Y, Tian H. Current development status of MEK inhibitors. Molecules. 2017;22(10):1-20.DOI: 10.3390/molecules22101551.

Jiang CH, Sun TL, Xiang DX, Wei SS, Li WQ. Anticancer activity and mechanism of xanthohumol: a prenylated flavonoid from hops (Humulus lupulus L.). Front Pharmacol. 2018;9(530):1-13.DOI: 10.3389/fphar.2018.00530.

Gholizadeh Siahmazgi Z, Irani S, Ghiaseddin A, Fallah P, Haghpanah V. Xanthohumol hinders invasion and cell cycle progression in cancer cells through targeting MMP2, MMP9, FAK and P53 genes in three-dimensional breast and lung cancer cells culture. Cancer Cell Int. 2023;23(1):153,1-11.DOI: 10.1186/s12935-023-03009-2.

Lee S, Rauch J, Kolch W. Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity. Int J Mol Sci. 2020;21(3):1102,1-29.DOI: 10.3390/ijms21031102.

Wishart DS. Bioinformatics in drug development and assessment. Drug Metab Rev. 2005;37(2):279-310.DOI: 10.1081/dmr-55225.

Hartung IV, Hitchcock M, Pühler F, Neuhaus R, Scholz A, Hammer S, et al. Optimization of allosteric MEK inhibitors. Part 1: venturing into underexplored SAR territories. Bioorganic Med Chem Lett. 2013;23(8):2384-2390.DOI: 10.1016/j.bmcl.2013.02.028.

Isfahani MB, Mahnam K, Seyedhosseini-Ghaheh H, Sadeghi HMM, Khanahmad H, Akbari V, et al. Computational design of newly engineered DARPins as HER2 receptor inhibitors for breast cancer treatment. Res Pharm Sci. 2023;18(6):626-637.DOI: 10.4103/1735-5362.389950.

Johansson MU, Zoete V, Michielin O, Guex N. Defining and searching for structural motifs using DeepView/Swiss-PdbViewer. BMC Bioinformatics. 2012;13:173,1-10. DOI: 10.1186/1471-2105-13-173.

Hashemi-shahraki F, Shareghi B, Farhadian S. The interaction of naphthol yellow S (NYS) with pepsin: insights from spectroscopic to molecular dynamics studies. Int J Biol Macromol. 2020;165:1842-1851. DOI: 10.1016/j.ijbiomac.2020.10.093.

Rajaei N, Rahgouy G, Panahi N, Razzaghi-Asl N. Bioinformatic analysis of highly consumed phytochemicals as P-gp binders to overcome drug-resistance. Res Pharm Sci. 2023;18(5):505-516. DOI: 10.4103/1735-5362.383706.

Tannas LE. System requirements. In: Flat-panel displays and CRTs. 1th ed. Dordrcecht: Springer; 1985.pp. 31-53.DOI: 10.1007/978-94-011-7062-8_2.

Messias A, Santod DES, Pontes FJS, Lima FS, Soares TA. Out of sight, out of mind: the effect of the equilibration protocol on the structural ensembles of charged glycolipid bilayers. Molecules. 2020;25(21):1-16.DOI: 10.3390/molecules25215120.

Hatami S, Sirous H, Mahnam K, Najafipour A, Fassihi A. Preparing a database of corrected protein structures important in cell signaling pathways. Res Pharm Sci. 2022;18(1):67-77.DOI: 10.4103/1735-5362.363597.

Han J, Liu Y, Yang S, Wu X, Li H, Wang Q. MEK inhibitors for the treatment of non-small cell lung cancer. J Hematol Oncol. 2021;14(1):1,1-12.DOI: 10.1186/s13045-020-01025-7.

Seitz T, Hackl C, Freese K, Dietrich P, Mahli A, Thasler RM, et al. Xanthohumol, a prenylated chalcone derived from hops, inhibits growth and metastasis of melanoma cells. Cancers (Basel). 2021;13(3):1-12.DOI: 10.3390/cancers13030511.

Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26(22):3291-3310.DOI: 10.1038/sj.onc.1210422.

Catling AD, Schaeffer HJ, Reuter CW, Reddy GR, Weber MJ. A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Mol Cell Biol. 1995;15(10):5214-5225.DOI: 10.1128/mcb.15.10.5214.

Gholizadeh Siahmazgi Z, Irani S, Ghiaseddin A, Fallah P, Haghpanah V. Bioinformatic study on effect of xanthohumol as bioactive compound of HOP in the inhibition of the MAPK/ERK pathway in thyroid cancer. Iran J Diabetes Metab. 2020;19(4):225-233.

Hashemzadeh S, Ramezani F, Rafii-Tabar H. Study of molecular mechanism of the interaction between MEK1/2 and trametinib with docking and molecular dynamic simulation. Interdiscip Sci Comput Life Sci. 2019;11(1):115-124.DOI: 10.1007/s12539-018-0305-4.

Zhu J, Li C, Yang H, Guo X, Huang T, Han W. Computational study on the effect of inactivating/ activating mutations on the inhibition of MEK1 by trametinib. Int J Mol Sci. 2020;21(6):2167,1-15.DOI: 10.3390/ijms21062167.

Fleischmann J, Feichtner A, Defalco L, Kugler V, Schwaighofer S, Huber RG, et al. Allosteric kinase inhibitors reshape mek1 kinase activity conformations in cells and in silico. Biomolecules. 2021;11(4):518,1-13.DOI: 10.3390/biom11040518.

Wu PK, Becker A, Park JI. Growth inhibitory signaling of the raf/mek/erk pathway. Int J Mol Sci. 2020;21(15):1-12.DOI: 10.3390/ijms21155436.

Roskoski Jr. MEK1/2 dual-specificity protein kinases: Structure and regulation. Biochem Biophys Res Commun. 2012;417(1):5-10.DOI: 10.1016/j.bbrc.2011.11.145.

Roskoski Jr. Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. Pharmacol Res. 2017;117:20-31.DOI: 10.1016/j.phrs.2016.12.009.

Liu X, An LJ, Li Y, Wang Y, Zhao L, Lv X, et al. Xanthohumol chalcone acts as a powerful inhibitor of carcinogenesis in drug-resistant human colon carcinoma and these effects are mediated via G2/M phase cell cycle arrest, activation of apoptotic pathways, caspase activation and targeting Ras /MEK/ERK pa. J BUON. 2019;24(6):2442-2447.PMID: 31983118.

Gao F, Li M, Zhou L, Liu W, Zuo H, Li W. Xanthohumol targets the ERK1/2-Fra1 signaling axis to reduce cyclin D1 expression and inhibit non-small cell lung cancer. Oncol Rep. 2020;44(4):1365-1374.DOI: 10.3892/or.2020.7697.

Lobanov Yu, Bogatyreva NS, Galzitskaya OV. Radius of gyration as an indicator of protein structure compactness. Mol Biol. 2008;42(4):623-628.

DOI: 10.1134/S0026893308040195.

Kim SB, Singh RS, Paul PKC, Debenedetti PG. Effects of disulfide bridges and backbone connectivity on water sorption by protein matrices. Sci Rep. 2017;7:7957,1-9.DOI: 10.1038/s41598-017-08561-2.

Malleshappa Gowder S, Chatterjee J, Chaudhuri T, Paul K. Prediction and analysis of surface hydrophobic residues in tertiary structure of proteins. Sci World J. 2014;2014:1-7.DOI: 10.1155/2014/971258.

Festa M, Capasso A, D’Acunto CW, Masullo M, Rossi AG, Pizza C, et al. Xanthohumol induces apoptosis in human malignant glioblastoma cells by increasing reactive oxygen species and activating MAPK pathways. J Nat Prod. 2011;74(12):2505-2513.DOI: 10.1021/np200390x.

Assadollahi V, Rashidieh B, Alasvand M, Abdolahi A, Lopez JA. Interaction and molecular dynamics simulation study of Osimertinib (AstraZeneca 9291) anticancer drug with the EGFR kinase domain in native protein and mutated L844V and C797S. J Cell

Biochem. 2019;120(8):13046-13055.DOI: 10.1002/jcb.28575.

Pace CN, Fu H, Fryar KL, Landua J, Trevino SR, Schell D, et al. Contribution of hydrogen bonds to protein stability. Protein Sci. 2014;23(5):652-661.DOI: 10.1002/pro.2449.

Koch O. Use of secondary structure element information in drug design: polypharmacology and conserved motifs in protein-ligand binding and protein-protein interfaces. Future Med Chem. 2011;3(6):699-708.DOI: 10.4155/fmc.11.26.


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