Abstract
CRC has a major global health impact due to high mortality rates. CRC shows high expression of eukaryotic translation initiation factor (eIF4E) protein, the rapid development of lung, bladder, colon, prostate, breast, head, and neck cancer is attributed to the dysregulation of eIF4E making an important target for treatment. Targeting eIF4E-mediated translation is a promising anti-cancer strategy. Many organic compounds that inhibit eIF4E are being studied clinically. The compound Sizofiran has emerged as a promising eIF4E inhibitor candidate, but its exact mechanism of action is unclear. In an effort to close this discrepancy by clarifying the mechanism of the interactions between phytochemical substances and eIF4E, molecular docking and dynamics studies were conducted. Molecular docking studies found Sizofiran (− 12.513 kcal/mol) has the most affinity eIF4E binding energy out of 93 phytochemicals, 5 current drugs, and 4 known inhibitors. This positions it as a top eIF4E inhibitor candidate. An alignment of eIF4E protein sequences from multiple pathogens revealed that the glutamate103 interacting residues are evolutionarily conserved across the different eIF4E proteins. Further insights from 100 ns of MD simulations supported Sizofiran having superior stability and eIF4E inhibition compared to reference compounds. Designed Sizofiran-related compounds showed better activity than the current drugs such as Camptosar, Sorafenib, Regorafenib, Doxorubicin, and Kenpaullone, indicating strong potential to suppress CRC progression by targeting eIF4E. This research aims to significantly aid development of improved eIF4E-targeting drugs for cancer treatment.
Graphical abstract
Showing the Graphical abstract of the complete study.
Similar content being viewed by others
Data Availability
Not Applicable.
Abbreviations
- CRC:
-
Colorectal cancer
- eIF4E:
-
Eukaryotic translation initiation factor
- MDS:
-
Molecular dynamics simulation
- RMSD:
-
Root mean square deviation
- RMSF:
-
Root mean square fluctuation
- Rg:
-
Radius of gyration
- SASA:
-
Solvent accessible surface area
References
Ahmad, S., Pasha KM, M., Raza, K., Rafeeq, M. M., Habib, A. H., Eswaran, M., & Yadav, M. K. (2022). Reporting dinaciclib and theodrenaline as a multitargeted inhibitor against SARS-CoV-2: an in-silico study. Journal of Biomolecular Structure and Dynamics, 41(9), 4013–4023. https://doi.org/10.1080/07391102.2022.2060308
Ahmad S, Raza K (2023) Identification of 5-nitroindazole as a multitargeted inhibitor for CDK and transferase kinase in lung cancer: a multisampling algorithm-based structural study. Mol Diversity. https://doi.org/10.1007/s11030-023-10648-0
Anandan S, Gowtham HG, Shivakumara CS, Thampy A, Singh SB, Murali M, Shivamallu C, Pradeep S, Shilpa N, Shati AA, Alfaifi, MY, Elbehairi SEI, Ortega-Castro J, Frau J, Flores-Holguín N, Kollur SP, Glossman-Mitnik D (2022) Integrated approach for studying bioactive compounds from Cladosporium spp. against estrogen receptor alpha as breast cancer drug target. Scientific Reports, 12(1). https://doi.org/10.1038/s41598-022-22038-x
Araghi M, Soerjomataram I, Jenkins M, Brierley J, Morris E, Bray F, Arnold M (2019) Global trends in colorectal cancer mortality: projections to the year 2035. Int J Cancer 144(12): 2992–3000. Portico. https://doi.org/10.1002/ijc.32055
Ashraf MA (2020) Phytochemicals as potential anticancer drugs: time to ponder nature’s bounty. Biomed Res Int 2020:1–7. https://doi.org/10.1155/2020/8602879
Atanasov AG, Zotchev SB, Dirsch VM, Supuran CT (2021) Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discovery 20(3):200–216. https://doi.org/10.1038/s41573-020-00114-z
Bhat M, Robichaud N, Hulea L, Sonenberg N, Pelletier J, Topisirovic I (2015) Targeting the translation machinery in cancer. Nat Rev Drug Discovery 14(4):261–278. https://doi.org/10.1038/nrd4505
Bitterman PB, Polunovsky VA (2015) eIF4E-mediated translational control of cancer incidence. Biochimica et Biophysica Acta (BBA)—Gene Regulatory Mechanisms, 1849(7), 774–780. https://doi.org/10.1016/j.bbagrm.2014.09.007
Borchers AT, Stern JS, Hackman RM, Keen CL, Gershwin ME (1999) Mushrooms, tumors, and immunity. Proceedings of the Society for Experimental Biology and Medicine, 221(4), 281–293. Portico. https://doi.org/10.1046/j.1525-1373.1999.d01-86.x
Carroll M, Borden KLB (2013) The Oncogene eIF4E: Using Biochemical Insights to Target Cancer. J Interferon Cytokine Res 33(5):227–238. https://doi.org/10.1089/jir.2012.0142
Chaichian S, Moazzami B, Sadoughi F, Haddad Kashani H, Zaroudi M, Asemi Z (2020) Functional activities of beta-glucans in the prevention or treatment of cervical cancer. J Ovarian Res 13(1). https://doi.org/10.1186/s13048-020-00626-7
Chen X, An Y, Tan M, Xie D, Liu L, Xu B (2023) Biological functions and research progress of eIF4E. Front Oncol 13. https://doi.org/10.3389/fonc.2023.1076855
Chen H, Panagiotopoulos AZ (2019) Molecular modeling of surfactant micellization using solvent-accessible surface area. Langmuir 35(6):2443–2450. https://doi.org/10.1021/acs.langmuir.8b03440
Chikalov I, Yao P, Moshkov M, Latombe J-C (2011) Learning probabilistic models of hydrogen bond stability from molecular dynamics simulation trajectories. BMC Bioinformatics, 12(S1). https://doi.org/10.1186/1471-2105-12-s1-s34
Choudhari AS, Mandave PC, Deshpande M, Ranjekar P, Prakash O (2020) Phytochemicals in cancer treatment: from preclinical studies to clinical practice. Front Pharmacol 10. https://doi.org/10.3389/fphar.2019.01614
Chu J, Cargnello M, Topisirovic I, Pelletier J (2016) Translation initiation factors: reprogramming protein synthesis in cancer. Trends Cell Biol 26(12):918–933. https://doi.org/10.1016/j.tcb.2016.06.005
Dong K, Wang R, Wang X, Lin F, Shen J-J, Gao P, Zhang H-Z (2008) Tumor-specific RNAi targeting eIF4E suppresses tumor growth, induces apoptosis and enhances cisplatin cytotoxicity in human breast carcinoma cells. Breast Cancer Res Treat 113(3):443–456. https://doi.org/10.1007/s10549-008-9956-x
Friesner RA, Murphy RB, Repasky MP, Frye LL, Greenwood JR, Halgren TA, Sanschagrin PC, Mainz DT (2006) Extra precision glide: docking and scoring incorporating a model of hydrophobic enclosure for protein−ligand complexes. J Med Chem 49(21):6177–6196. https://doi.org/10.1021/jm051256o
Gorai I, Yanagibashi T, Minaguchi H (1992) Immunological modulation of lymphocyte subpopulation in cervical cancer tissue by sizofiran and OK-432. Gynecol Oncol 44(2):137–146. https://doi.org/10.1016/0090-8258(92)90029-i
Halgren TA (2009) Identifying and characterizing binding sites and assessing druggability. J Chem Inf Model 49(2):377–389. https://doi.org/10.1021/ci800324m
Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (1997) LINCS: a linear constraint solver for molecular simulations. J Comput Chem 18(12): 1463–1472. https://doi.org/10.1002/(sici)1096-987x(199709)18:12<1463::aid-jcc4>3.3.co;2-l
Ikwu FA, Isyaku Y, Obadawo BS, Lawal HA, Ajibowu SA (2020) In silico design and molecular docking study of CDK2 inhibitors with potent cytotoxic activity against HCT116 colorectal cancer cell line. J Genetic Eng Biotechnol 18(1):51. https://doi.org/10.1186/s43141-020-00066-2
Kandakatla N, Ramakrishnan G (2014) Ligand based pharmacophore modeling and virtual screening studies to design novel HDAC2 inhibitors. Adv Bioinform 2014:1–11. https://doi.org/10.1155/2014/812148
Katz SI, Cooper KD, Iijima M, Tsuchida T (1985) The role of langerhans cells in antigen presentation. J Investig Dermatol 85(1):S96–S98. https://doi.org/10.1111/1523-1747.ep12275562
Kawata M, Mikami M (2001) Rapid calculation of two-dimensional Ewald summation. Chem Phys Lett 340(1–2):157–164. https://doi.org/10.1016/s0009-2614(01)00378-5
Kikumoto S, Miyajima T, Kimura K, Okubo S, Komatsu N (1971) Polysaccharide produced by schizophyllum commune Part II. J Agricult Chem Soc Jpn 45(4):162–168. https://doi.org/10.1271/nogeikagaku1924.45.162
Kolligs, F. T. (2016). Diagnostics and epidemiology of colorectal cancer. Visceral Med, 32(3), 158–164. Portico. https://doi.org/10.1159/000446488
Lobanov MYu, Bogatyreva NS, Galzitskaya OV (2008) Radius of gyration as an indicator of protein structure compactness. Mol Biol 42(4):623–628. https://doi.org/10.1134/s0026893308040195
Mansour A, Daba A, Baddour N, El-Saadani M, Aleem E (2012) Schizophyllan inhibits the development of mammary and hepatic carcinomas induced by 7,12 dimethylbenz(α)anthracene and decreases cell proliferation: comparison with tamoxifen. J Cancer Res Clin Oncol 138(9):1579–1596. https://doi.org/10.1007/s00432-012-1224-0
McDonald IR (1972) NpT-ensemble Monte Carlo calculations for binary liquid mixtures. Mol Phys 23(1):41–58. https://doi.org/10.1080/00268977200100031
Meng X, Liang H, Luo L (2016) Antitumor polysaccharides from mushrooms: a review on the structural characteristics, antitumor mechanisms and immunomodulating activities. Carbohyd Res 424:30–41. https://doi.org/10.1016/j.carres.2016.02.008
Miyamoto, S., & Kollman, P. A. (1992). Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models. Journal of Computational Chemistry, 13(8), 952–962. Portico. https://doi.org/10.1002/jcc.540130805
Mizuhira V, Ono M, Yokofujita J, Kinoshita M, Asano T, Hase T, Amemiya K (1985) Histological and cytochemical studies on the distribution of schizophyllan glucan (SPG) in cancer-inoculated animals. I. Differences in distribution and antitumor activity of 3H-SPG in sarcoma-180 inoculated females between ICR and DBA mice. Acta Histochemica et Cytochemica, 18(2), 221–254. https://doi.org/10.1267/ahc.18.221
Muhammad S, Saba A, Khera RA, Al-Sehemi Abdullah G, Algarni H, Iqbal J, Alshahrani MY, Chaudhry AR (2022) Virtual screening of potential inhibitor against breast cancer-causing estrogen receptor alpha (ERα): molecular docking and dynamic simulations. Molecular Simulation, 48(13), 1163–1174. https://doi.org/10.1080/08927022.2022.2072840
Nakano T, Oka K, Hanba K, Morita S (1996) Intratumoral administration of sizofiran activates langerhans cell and T-cell infiltration in cervical cancer. Clin Immunol Immunopathol 79(1):79–86. https://doi.org/10.1006/clin.1996.0053
Nemoto J, Ohno N, Saito K, Adachi Y, Yadomae T (1994) Analysis of Cytokine mRNAs Induced by the Administration of a Highly Branched (1.RAR.3)-.BETA.-D-Glucan, OL-2. Biol Pharmaceutical Bull 17(7): 948–954. https://doi.org/10.1248/bpb.17.948
Niu Z, Wang J, Muhammad S, Niu W, Liu E, Peng C, Liang B, Sun Q, Obo S, He Z, Liu S, Zou X, Niu J (2014) Protein expression of eIF4E and integrin αvβ6 in colon cancer can predict clinical significance, reveal their correlation and imply possible mechanism of interaction. Cell Biosci 4(1):23. https://doi.org/10.1186/2045-3701-4-23
Pradeep S, Jain AS, Dharmashekara C, Prasad SK, Akshatha N, Pruthvish R, Amachawadi RG, Srinivasa C, Syed A, Elgorban AM, Al Kheraif AA, Ortega-Castro J, Frau J, Flores-Holguín N, Shivamallu C, Kollur SP, Glossman-Mitnik D (2021) Synthesis, computational pharmacokinetics report, conceptual DFT-based calculations and anti-acetylcholinesterase activity of hydroxyapatite nanoparticles derived from acorus calamus plant extract. Front Chem 9. https://doi.org/10.3389/fchem.2021.741037
Prasad SK, Pradeep S, Shimavallu C, Kollur SP, Syed A, Marraiki N, Egbuna C, Gaman M-A, Kosakowska O, Cho WC, Patrick-Iwuanyanwu KC, Ortega Castro J, Frau J, Flores-Holguín N, Glossman-Mitnik D (2021) Evaluation of annona muricata acetogenins as potential anti-SARS-CoV-2 agents through computational approaches. Frontiers in Chemistry, 8. https://doi.org/10.3389/fchem.2020.624716
Ramírez D, Caballero J (2018) Is it reliable to take the molecular docking top scoring position as the best solution without considering available structural data? Molecules 23(5):1038. https://doi.org/10.3390/molecules23051038
Rasul HO, Aziz BK, Ghafour DD, Kivrak A (2022a) Screening the possible anti-cancer constituents of Hibiscus rosa-sinensis flower to address mammalian target of rapamycin: an in silico molecular docking, HYDE scoring, dynamic studies, and pharmacokinetic prediction. Mol Diversity 27(5):2273–2296. https://doi.org/10.1007/s11030-022-10556-9
Rasul HO, Aziz BK, Ghafour DD, Kivrak A (2022b) Discovery of potential mTOR inhibitors from Cichorium intybus to find new candidate drugs targeting the pathological protein related to the breast cancer: an integrated computational approach. Mol Diversity 27(3):1141–1162. https://doi.org/10.1007/s11030-022-10475-9
Release, S. (2017). LigPrep (Vol. 2). Schrodinger, LLC
Repasky, M. P., Shelley, M., & Friesner, R. A. (2007). Flexible Ligand Docking with Glide. Current Protocols in Bioinformatics, 18(1). Portico. https://doi.org/10.1002/0471250953.bi0812s18
Robert X, Gouet P (2014) Deciphering key features in protein structures with the new ENDscript server. Nucleic Acids Res 42(W1):W320–W324. https://doi.org/10.1093/nar/gku316
Romagnoli A, D’Agostino M, Ardiccioni C, Maracci C, Motta S, La Teana A, Di Marino D (2021) Control of the eIF4E activity: structural insights and pharmacological implications. Cell Mol Life Sci 78(21–22):6869–6885. https://doi.org/10.1007/s00018-021-03938-z
Ruan H, Li X, Xu X, Leibowitz BJ, Tong J, Chen L, Ao L, Xing W, Luo J, Yu Y, Schoen RE, Sonenberg N, Lu X, Zhang L, Yu J (2020) eIF4E S209 phosphorylation licenses myc- and stress-driven oncogenesis. ELife, 9. CLOCKSS. https://doi.org/10.7554/elife.60151
Samykannu G, Vijayababu P, Antonyraj CB, Narayanan S, Basheer Ahamed SI (2017) Investigations of binding mode insight in Salmonella typhi type-III secretion system tip protein (SipD): a molecular docking and MD simulation study. Inform Med Unlocked 9:166–172. https://doi.org/10.1016/j.imu.2017.08.002
Samykannu G, Vijayababu P, Natarajan J (2019a) Substrate specificities in Salmonella typhi outer membrane protease (PgtE) from omptin family—An in silico proteomic approach. Informatics in Medicine Unlocked 16:100237. https://doi.org/10.1016/j.imu.2019.100237
Samykannu G, Vijayababu P, Antonyraj CB, Perumal P, Narayanan S, Basheer Ahamed SI, Natarajan J (2019b) In silico characterization of B cell and T cell epitopes for subunit vaccine design ofSalmonella typhiPgtE: a molecular dynamics simulation approach. J Comput Biol 26(2):105–116. https://doi.org/10.1089/cmb.2018.0010
Samykannu G, Vijayababu P, Antonyraj CB, Narayanan S (2020) Structural investigation of APRs to improve the solubility of outer membrane protease (PgtE) from Salmonella enterica serotype typhi- A multi-constraint approach. Biochem Biophys Rep 21:100693. https://doi.org/10.1016/j.bbrep.2019.100693
Schrodinger Release (2020). 1: Prime. Schrodinger, LLC https://www.schrodinger.com/citations.
Schrodinger Release. (2020). 4: Glide. Schrodinger, LLC. 757
Shimizu Y, Hasumi K, Masubuchi K (1992) Augmenting effect of sizofiran on the bmmunofunction of regional lymph nodes in cervical cancer. Cancer, 69(5): 1188–1194. Portico. https://doi.org/10.1002/cncr.2820690520
Shivakumar D, Williams J, Wu Y, Damm W, Shelley J, Sherman W (2010) Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field. J Chem Theory Comput 6(5):1509–1519. https://doi.org/10.1021/ct900587b
Siegel RL, Miller KD, Jemal A (2020) Cancer statistics, 2020. CA: A Cancer Journal for Clinicians, 70(1), 7–30. Portico. https://doi.org/10.3322/caac.21590
Simon L, Imane A, Srinivasan KK, Pathak L, Daoud I (2016) In Silico drug-designing studies on flavanoids as anticolon cancer agents: pharmacophore mapping, molecular docking, and monte carlo method-based QSAR modeling. Interdisciplinary Sci 9(3):445–458. https://doi.org/10.1007/s12539-016-0169-4
Soukarieh F, Nowicki MW, Bastide A, Pöyry T, Jones C, Dudek K, Patwardhan G, Meullenet F, Oldham NJ, Walkinshaw MD, Willis AE, Fischer PM (2016) Design of nucleotide-mimetic and non-nucleotide inhibitors of the translation initiation factor eIF4E: Synthesis, structural and functional characterisation. Eur J Med Chem 124:200–217. https://doi.org/10.1016/j.ejmech.2016.08.047
Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJC (2005) GROMACS: Fast, flexible, and free. J Comput Chem 26(16): 1701–1718. Portico. https://doi.org/10.1002/jcc.20291
Vijayababu P, Samykannu G, Thomas J, Antonyraj CB, Narayanan S, Piramanayagam S (2019) Patulin interference with ATP binding cassette transferring auto inducer—2 in Salmonella typhi and biofilm inhibition via quorum sensing. Informatics Med Unlocked 16:100230. https://doi.org/10.1016/j.imu.2019.100230
Xu Y, Ruggero D (2020) The role of translation control in tumorigenesis and its therapeutic implications. Ann Rev Cancer Biol 4(1):437–457. https://doi.org/10.1146/annurev-cancerbio-030419-033420
Yadav MK, Ahmad S, Raza K, Kumar S, Eswaran M, Pasha KM, M. (2022) Predictive modeling and therapeutic repurposing of natural compounds against the receptor-binding domain of SARS-CoV-2. Journal of Biomolecular Structure and Dynamics, 41(5), 1527–1539. https://doi.org/10.1080/07391102.2021.2021993
Yang J, Roy A, Zhang Y (2013) Protein–ligand binding site recognition using complementary binding-specific substructure comparison and sequence profile alignment. Bioinformatics 29(20):2588–2595. https://doi.org/10.1093/bioinformatics/btt447
Yang X, Zang J, Pan X, Yin J, Xiang Q, Yu J, Gan R, Lei X (2016) miR-503 inhibits proliferation making human hepatocellular carcinoma cells susceptible to 5-fluorouracil by targeting EIF4E. Oncol Rep 37(1):563–570. https://doi.org/10.3892/or.2016.5220
Acknowledgements
Authors are thankful to DST-FIST, for providing the necessary infrastructure.
Author information
Authors and Affiliations
Contributions
Gopinath: Structurebased virtual screening, Molecular docking, Manuscript preparation. Nandhini: Molecular Dynamics and Editing. Jeyakumar: Idea generation, Review & Editing, and Overall supervision.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Samykannu, G., Mariyappan, N. & Natarajan, J. Molecular interaction and MD-simulations: investigation of Sizofiran as a promising anti-cancer agent targeting eIF4E in colorectal cancer. In Silico Pharmacol. 12, 33 (2024). https://doi.org/10.1007/s40203-024-00206-3
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40203-024-00206-3