Molecular Docking Studies of Spirostans as MAPK14 (P38α) Inhibitors and Their Potential Use against Cancer
DOI:
https://doi.org/10.33084/jmd.v1i2.2904Keywords:
Molecular docking, Spirostans, MAPK14 inhibitionAbstract
Spirostans (SPs) are chemical products widely distributed in the plant kingdom; currently, they are studied by their medical applications. Cancer has a high incidence in humans; it reaches second place worldwide deaths. In molecular biology, it has been accepted that Mitogen-Activated Protein p38alpha Kinase (MAPK14 (p38α) is implicated in the regulation of cancer. This study aimed to identify SPs as potential MAPK14 (p38α) inhibitors. From a set of 133 modified SPs, SwissTargetPrediction platform, and molecular docking, it was obtained that 129 chemical structures had molecular interaction with the MAPK14 (p38α). From those molecules, 123 were bound to a specific inhibition site of MAPK14 (p38α), and 6 of the structures resulted in inhibitors similarly to minocycline and dasatinib. One SP had binding couple energy (BCE, kcal/mol) as that of fostamatinib. In addition, 115 modified SPs had better BCE than the minocycline but not as that using fostamatinib. The key amino acids (aa) for the protein kinase MAPK14 (p38α) inhibition were Arg 70, Asp 168, Lys 53, His 148, and Ile 145, at a different interaction level. The BCE was enhanced when the H atom was substituted in C-2, C-11, and C-17 SPs positions. Similarly, the αOH group at C-5 and C-6 upgraded BCE. Stereochemistry and substitution at C-3, C-12, and C-25 did not present significant differences (Kruskal-Wallis test, p <0.05). From all this ensemble of results, it is foreseeable that the SPs can be an option for MAPK14 (p38α) inhibition, a key modulator in cancer processes.
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References
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2. Tang ZZ, Zhang YM, Zheng T, Huang TT, Ma TF, Liu YW. Sarsasapogenin alleviates diabetic nephropathy through suppression of chronic inflammation by down-regulating PAR-1: In vivo and in vitro study. Phytomedicine. 2020;78:153314. doi:10.1016/j.phymed.2020.153314
3. Liagre B, Vergne-Salle P, Leger DY, Beneytout JL. Inhibition of human rheumatoid arthritis synovial cell survival by hecogenin and tigogenin is associated with increased apoptosis, p38 mitogen-activated protein kinase activity and upregulation of cyclooxygenase-2. Int J Mol Med. 2007;20(4):451-60. doi:10.3892/ijmm.20.4.451
4. Wang W, Zhang Y, Yao G, Wang W, Shang X, Zhang Y, et al. Synthesis of new sarsasapogenin derivatives with antiproliferative and apoptotic effects in MCF-7 cells. Steroids. 2018;131:23-31. doi:10.1016/j.steroids.2018.01.001
5. Hilario-Martínez JC, Huerta A, Amaro-López JC, Alatriste V, De los Santos MG, Martínez I, et al. Stereoselective synthesis of (26R)-26-hydroxydiosgenin and its effect on the regulation of rat ovarian function. Bioorg Chem. 2021;115:105189. doi:10.1016/j.bioorg.2021.105189
6. Sánchez-Sánchez L, Escobar ML, Sandoval-Ramírez J, López-Muñoz H, Fernández-Herrera MA, Hernández-Vázquez JMV, et al. Apoptotic and autophagic cell death induced by glucolaxogenin in cervical cancer cells. Apoptosis. 2015;20(12):1623-35. doi:10.1007/s10495-015-1181-6
7. Hernández-Vázquez JMV, López-Muñoz H, Escobar-Sánchez ML, Flores-Guzmán F, Weiss-Steider B, Hilario-Martínez JC, et al. Apoptotic, necrotic, and antiproliferative activity of diosgenin and diosgenin glycosides on cervical cancer cells. Eur J Pharmacol. 2020;871:172942. doi:10.1016/j.ejphar.2020.172942
8. Escobar-Sánchez ML, Sánchez-Sánchez L, Sandoval-Ramírez J. Steroidal Saponins and Cell Death in Cancer, Cell Death - Autophagy, Apoptosis and Necrosis. IntechOpen. 2015. p. 331-51. doi:10.5772/61438
9. Carrasco-Carballo A, Hernández-Linares MG, Cárdenas-García M, Sandoval-Ramírez J. Synthesis and biological in vitro evaluation of the effect of hydroxyimino steroidal derivatives on breast cancer cells. Steroids. 2021;166:108787. doi:10.1016/j.steroids.2020.108787
10. Corbière C, Liagre B, Bianchi A, Bordji K, Dauça M, Netter P, et al. Different contribution of apoptosis to the antiproliferative effects of diosgenin and other plant steroids, hecogenin and tigogenin, on human 1547 osteosarcoma cells. Int J Oncol. 2003;22(4):899-905. doi:10.3892/ijo.22.4.899
11. Acharya D, Mitaine-Offer AC, Kaushik N, Miyamoto T, Paululat T, Mirjolet JF, et al. Cytotoxic spirostane-type saponins from the roots of Chlorophytum borivilianum. J Nat Prod. 2009;72(1):177-81. doi:10.1021/np800559z
12. Wang W, Meng H. Cytotoxic, anti-inflammatory and hemostatic spirostane-steroidal saponins from the ethanol extract of the roots of Bletilla striata. Fitoterapia. 2015;101:12-8. doi:10.1016/j.fitote.2014.11.005
13. Xu XH, Li T, Fong CMV, Chen X, Chen XJ, Wang YT, et al. Saponins from Chinese medicines as anticancer agents. Molecules. 2016;21(10):1326. doi:10.3390/molecules21101326
14. Cuenda A, Rousseau S. p38 MAP-Kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta. 2007;1773(8):1358-75. doi:10.1016/j.bbamcr.2007.03.010
15. Liu J, Yu X, Yu H, Liu B, Zhang Z, Kong C, et al. Knockdown of MAPK14 inhibits the proliferation and migration of clear cell renal cell carcinoma by downregulating the expression of CDC25B. Cancer Med. 2020;9(3):1183-95. doi:10.1002/cam4.2795
16. Yang L, Sun X, Ye Y, Lu Y, Zuo J, Liu W, et al. p38α Mitogen-Activated Protein Kinase Is a Druggable Target in Pancreatic Adenocarcinoma. Front Oncol. 2019;9:1294. doi:10.3389/fonc.2019.01294
17. Mesquita FP, Moreira-Nunes CA, da Silva EL, Lima LB, Daniel JP, Zuerker WJ, et al. MAPK14 (p38α) inhibition effects against metastatic gastric cancer cells: A potential biomarker and pharmacological target. Toxicol In Vitro. 2020;66:104839. doi:10.1016/j.tiv.2020.104839
18. Dashti S, Taherian-Esfahani Z, Kholghi-Oskooei V, Noroozi R, Arsang-Jang S, Ghafouri-Fard S, et al. In silico identification of MAPK14-related lncRNAs and assessment of their expression in breast cancer samples. Sci Rep. 2020;10:8316. doi:10.1038/s41598-020-65421-2
19. Ding QY, Zhang Y, Ma L, Chen YG, Wu JH, Zhang HF, et al. Inhibiting MAPK14 showed anti-prolactinoma effect. BMC Endocr Disord. 2020;20:138. doi:10.1186/s12902-020-00619-z
20. Gu L, Tao X, Xu Y, Han X, Qi Y, Xu L, et al. Dioscin alleviates BDL- and DMN-induced hepatic fibrosis via Sirt1/Nrf2-mediated inhibition of p38 MAPK pathway. Toxicol Appl Pharmacol. 2016;292:19–29. doi:10.1016/j.taap.2015.12.024
21. Daina A, Michielin O, Zoete V. SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res. 2019;47(W1):W357-W364. doi:10.1093/nar/gkz382
22. Sanner MF, Jolla L. News and Views. J Mol Graph Model. 1999;17(1):55–84. doi:10.1016/S1093-3263(99)99999-0
23. Trott O, Olson AJ. Software News and Update AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization, and Multithreading. J Comput Chem. 2010;31:455-61. doi:10.1002/jcc.21334
24. Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46(D1):D1074-D1082. doi:10.1093/nar/gkx1037
25. Röhm S, Schröder M, Dwyer JE, Widdowson CS, Chaikuad A, Berger BT, et al. Selective targeting of the αC and DFG-out pocket in p38 MAPK. Eur J Med Chem. 2020;208:112721. doi:10.1016/j.ejmech.2020.112721
26. Allinger NL. Conformational analysis. 130. MM2. A hydrocarbon force field utilizing V1 and V2 torsional terms. J Am Chem Soc. 1977;99(25):8127-34. doi:10.1021/ja00467a001
27. Kruskal WH, Wallis WA. Use of Ranks in One-Criterion Variance Analysis. J Am Stat Assoc. 1952;47(260):583-621. doi:10.2307/2280779
28. Lee KH, Schnupf U, Sumpter BG, Irle S. Performance of Density-Functional Tight-Binding in Comparison to Ab Initio and First-Principles Methods for Isomer Geometries and Energies of Glucose Epimers in Vacuo and Solution. ACS Omega. 2018;3(12):16899-915. doi:10.1021/acsomega.8b02213
29. Qiu L, Lin J, Liu Q, Wang S, Lv G, Li K, et al. The Role of the Hydroxyl Group in Propofol-Protein Target Recognition: Insights from ONIOM Studies. J Phys Chem B. 2017;121(24):5883-96. doi:10.1021/acs.jpcb.7b02079
30. Torres PHM, Sodero ACR, Jofily P, Silva Jr FP. Key Topics in Molecular Docking for Drug Design. Int J Mol Sci. 2019;20(18):4574. doi:10.3390/ijms20184574
31. Miller WL, Auchus RJ. The molecular biology, biochemistry, and physiology of human steroidogenesis and its disorders. Endocr Rev. 2011;32(1):81-151. doi:10.1210/er.2010-0013
32. Erbas-Cakmak S, Leigh DA, McTernan CT, Nussbaumer AL. Artificial Molecular Machines. Chem Rev. 2015;115(18):10081-206. doi:10.1021/acs.chemrev.5b00146
33. Sarkar A, Kellogg GE. Hydrophobicity--shake flasks, protein folding and drug discovery. Curr Top Med Chem. 2010;10(1):67-83. doi:10.2174/156802610790232233
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Published
2021-12-30
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Lopez-Castillo GN, Alatriste V, Sandoval-Ramírez J, Luna F, Carrasco-Carballo A. Molecular Docking Studies of Spirostans as MAPK14 (P38α) Inhibitors and Their Potential Use against Cancer. J Mol Docking [Internet]. 2021Dec.30 [cited 2024Nov.15];1(2):59-67. Available from: https://journal.umpr.ac.id/index.php/jmd/article/view/2904
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