Jeffry Julianus, Jumina, Mustofa
Jeffry Julianus1,2*, Jumina3, Mustofa4
1Doctoral Program in Faculty of Medicine, Public Health and Nursing, Gadjah Mada University,Yogyakarta, Indonesia.
2Department of Organic Chemistry, Faculty of Pharmacy, Sanata Dharma University, Yogyakarta, Indonesia.
3Department of Chemistry, Faculty of Mathematics and Natural Sciences, Gadjah Mada University, Yogyakarta, Indonesia.
4Department of Pharmacology and Therapy, Faculty of Medicine, `Public Health and Nursing, Gadjah Mada University, Yogyakarta, Indonesia.
Volume - 14,
Issue - 6,
Year - 2021
The existence of a large number of mutant p53 in cancer cell nuclei gives a poor prognosis. However, mutant p53 existence creates a challenge to design a new anticancer compound targeted to mutant p53. The 3-carbethoxy-4-phenyl-but-3-en-2-one is a novel compound that was designed as an anticancer agent targeted to mutant p53. Further evaluation of this compound was done by in silico examination employing Auto Dock Vina as molecular docking software. Molecular docking results denoted that 3-carbethoxy-4-phenyl-but-3-en-2-one had lower binding energy than methylene quinuclidinone (MQ). Visual inspection of the docking results denoted that 3-carbethoxy-4-phenyl-but-3-en-2-one docked in the binding pocket crystal structures of mutant p53 (2BIM, 2J1Y, and 2J21), forming a hydrogen bonding or hydrophobic interaction with Cys-124, and the distance between double bonds of a, ß-unsaturated of 3-carbethoxy-4-phenyl-but-3-en-2-one with –SH group of Cys-124 were shorter than MQ. These results demonstrated that 3-carbethoxy-4-phenyl-but-3-en-2-one is a promising ligand to mutant p53 in many types of mutations and predicted to have better activity than MQ as a mutant p53 reactivator especially in cancers with mutation type Arg-273-His and Arg-245-Trp.
Cite this article:
Jeffry Julianus, Jumina, Mustofa. Comparison of 3-carbethoxy-4-phenyl-but-3-en-2-one and methylene quinuclidinone as a ligand to reactivate mutant p53: molecular docking study in three types of crystal structure mutant p53: 2BIM, 2JIY, and 2J21. Research Journal of Pharmacy and Technology. 2021; 14(6):3358-4. doi: 10.52711/0974-360X.2021.00584
Jeffry Julianus, Jumina, Mustofa. Comparison of 3-carbethoxy-4-phenyl-but-3-en-2-one and methylene quinuclidinone as a ligand to reactivate mutant p53: molecular docking study in three types of crystal structure mutant p53: 2BIM, 2JIY, and 2J21. Research Journal of Pharmacy and Technology. 2021; 14(6):3358-4. doi: 10.52711/0974-360X.2021.00584 Available on: https://rjptonline.org/AbstractView.aspx?PID=2021-14-6-74
1. Nandhini S, Radha R, Vadivu R. Docking of hematoporphyrin on various anticancer drugs targeting enzymes. Asian Journal of Pharmaceutical Research. 2016; 6(3): 123-130.
2. Murugan V, Revathi S, Sumathi K, Geetha KM, Divekar K. Synthesis of some 1-[bis-N, N-(2-chloroethyl)aminoacetyl]-3,5-disubstituted-1,2-pyrazolines as possible alkylating anticancer agents. Asian Journal of Research in Chemistry. 2010; 3(2): 496-499.
3. Patil SD, Vinayak K, Balsubraniyan, Anwar S. Docking studies and synthesis of novel flavones screened for biological activities like anticancer and antioxidant activity. Asian Journal of Research in Chemistry. 2015; 8(6): 399-406.
4. Bray F. Transitions in human development and the global cancer burden. In: Wild CP, Stewart B, eds. World Cancer Report 2014. Lyon: International Agency for Research on Cancer. 2014.
5. World Health Organization. Cancer. 2018. Available from: URL: https://www.who.int/mediacentre/factsheets/fs297/en/.
6. Otuokere IE, Amaku FJ, Alisa CO. In silico geometry optimization, excited-state properties of (2E)-N-hydroxy-3-[3-(phenylsulfamoyl)phenyl]prop-2-enamide (belinostat) and its molecular docking studies with ebola virus glycoprotein. Asian Journal of Pharmaceutical Research. 2015; 5(3): 131-137.
7. Hemalatha K, Selvin J, Girija K. In silico molecular docking study and anti-bacterial evaluation of some novel 4-anilino quinazolines. Asian Journal of Pharmaceutical Research. 2018; 8(3): 125-132.
8. Hemalatha K, Girija K. Evaluation of drug candidature of some benzimidazole derivatives as biotin carboxylase inhibitors: molecular docking and insilico studies. Asian Journal of Research in Pharmaceutical Sciences. 2016; 6(1): 15-20.
9. Devgan M. Homology modeling and molecular docking studies of DNA replication licensing factor minichromosome maintenance protein 5 (MCM5). Asian Journal of Pharmacy and Technology. 2015; 5(1): 17-22.
10. Sindhu TJ, Arathi KN, Akhilesh KJ, Jose A, Binsiya KP, Thomas B, Wilson E. Antiviral screening of clerodol derivatives as COV 2 main protease inhibitor in novel corona virus disease: in silico approach. Asian Journal of Pharmacy and Technology. 2020; 10(2): 60-64.
11. Sravani M, Duganath N, Gade DR, Sandeep RCH. Insilico analysis and docking of imatinib derivatives targeting BCR-ABL oncoprotein for chronic myeloid leukemia. Asian Journal of Research in Chemistry. 2012; 5(1): 153-158.
12. Dhananjayan K, Sumathy A, Palanisamy S. Molecular docking studies and in-vitro acethylcholinesterase inhibition by terpenoids and flavonoids. Asian Journal of Research in Chemistry. 2013; 6(11): 1011-1017.
13. Valluri KK, Allaka TR, Viswanath IVK, Nagaraju PVVS. Design, molecular docking studies of oxaprozin linked to 4-thiazolidinone derivatives as a potent anticancer, analgesic and antiinflamatory agents. Asian Journal of Research in Chemistry. 2018; 11(3): 617-627.
14. Yue X, Zhao Y, Xu Y, Zheng M, Feng Z, Hu W. Mutant p53 in cancer: accumulation, gain-of-function, and therapy. Journal of Molecular Biology. 2017; 429(11): 1595–1606.
15. Hanel W, Marchenko N, Xu S, Xiaofeng Yu S, Weng W, Moll U. Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis. Cell Death and Differentiation. 2013; 20(7): 898–909.
16. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, Xie M, Zhang Q, McMichael JF, Wyczalkowski MA, Leiserson MDM, Miller CA, Welch JS, Walter MJ, Wendi MC, Ley TJ, Wilson RK, Raphael BJ, Ding L. Mutational landscape and significance across 12 major cancer types. Nature. 2013; 502: 333-339.
17. Muller PAJ, Vousden KH. P53 mutations in cancer. Nature Cell Biology. 2013; 15(1): 2–8.
18. Levine AJ, Hu W, Feng Z. The P53 pathway: what questions remain to be explored? Cell Death and Differentiation. 2006; 13(6): 1027–1036.
19. Haupt S, Raghu D, Haupt Y. Mutant p53 drives cancer by subverting multiple tumor suppression pathways. Frontiers in Oncology. 2016; 6(JAN): 1–7.
20. El-Deiry WS. The role of p53 in chemosensitivity and radiosensitivity. Oncogene. 2003; 22(47 REV. ISS. 6): 7486–7495.
21. Wassman CD, Baronio R, Demir O, Wallentine BD, Chen C-K, Hall LV, Salehi F, Lin D-W, Chung BP, Hatfield GW, Chamberlin AR, Luecke H, Lathrop RH, Kaiser P, Amaro RE. Computational identification of a transiently open L1/S3 pocket for reactivation of mutant p53. Nature Communications. 2013; 4: 1-9.
22. Zhang Q, Bykov VJN, Wiman KG, Zawacka-Pankau J. APR-246 reactivates mutant p53 by targeting cysteines 124 and 277. Cell Death Discovery. 2018; 9(5): 1-12.
23. Kaar JL, Basse N, Joerger AC, Stephens E, Rutherford TJ, Fersht AR. Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding. Protein Science. 2010; 19(12): 2267–2278.
24. Punganuru SR, Madala HR, Venugopal SN, Samala R, Mikelis C, Srivenugopal KS. Design, and synthesis of a C7-aryl piperlongumine derivative with potent antimicrotubule and mutant p53-reactivating properties. European Journal of Medicinal Chemistry. 2016; 107: 233–244.
25. Lehmann BD, Pietenpol JA. Targeting mutant p53 in human tumors. Journal of Clinical Oncology. 2012; 30(29): 3648–3650.
26. Joerger AC, Fersht AR. Structure-function-rescue: The diverse nature of common p53 cancer mutants. Oncogene. 2007; 26(15): 2226–2242.
27. Ventura A, Kirsch DG, McLaughlin ME, Tuveson DA, Grimm J, Lintault L, Newman J, Reczek EE, Weissleder R, Jacks T. Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128): 661–665.
28. Xue W, Zender L, Miething C, Dickins RA, Hernando E, Krizhanovsky V, Cordon-Cardo C, Lowe SW. Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445: 656-660.
29. Nguyen D, Liao W, Zeng SX, Lu H. Reviving the guardian of the genome: small molecule activators of p53. Pharmacology and Therapeutics. 2017; 178: 92–108.
30. Olivier M, Hollstein M, Hainaut P. TP53 mutations in human cancers: origins, consequences, and clinical use. Cold Spring Harbor Perspective in Biology. 2010; 2: 1-17.
31. Oren M, Tal P, Rotter V. Targeting mutant p53 for cancer therapy. Aging. 2016; 7(8): 1159–1160.
32. Kogan S, Carpizo D. Pharmacological targeting of mutant p53. Translational Cancer Research. 2016; 5(6): 698–706.
33. Ribeiro CJA, Rodrigues CMP, Moreira R, Santos MMM. Chemical variations on the p53 reactivation theme. Pharmaceuticals. 2016; 9(2): 1-33.
34. Trott O, Olson A. Autodock vina: improving the speed and accuracy of docking. Journal Computational Chemistry. 2010; 31(2): 455–461.
35. Lambert JMR, Gorzov P, Veprintsev DB, Söderqvist M, Segerbäck D, Bergman J, Fersht AR, Hainaut P, Wiman KG, Bykov VJN. PRIMA-1 reactivates mutant p53 by covalent binding to the core domain. Cancer Cell. 2009; 15(5): 376–388.
36. Bykov VJN, Zhang Q, Zhang M, Ceder S, Abrahmsen L, Wiman KG. Targeting of mutant P53 and the cellular redox balance by APR-246 as a strategy for efficient cancer therapy. Frontiers in Oncology. 2016; 6(FEB): 17–23.
37. Joerger AC, Hwee CA, Veprintsev DB, Blair CM, Fersht AR., Structures of p53 cancer mutants and mechanism of rescue by second-site suppressor mutations. Journal of Biological Chemistry. 2005; 280(16): 16030–16037.
38. Joerger AC, Ang HC, Fersht AR. Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proceedings of the National Academy of Science. 2006; 103(41): 15056–15061.
39. ChemAxon was used for energy minimization. MarvinSketch. 18.25. ChemAxon (https://www.chemaxon.com).
40. Dassault Systems BIOVIA. Discovery Studio Visualizer. V.17.2.0. San Diego: Dassault Systems. 2016.
41. Laskowski RA, Swindells MB. LigPlot+: multiple ligand-protein interaction diagrams for drug discovery. Journal of Chemical Information and Modeling. 2011; 51: 2778–2786.
42. Leroy B, Fournier JL, Ishioka C, Monti P, Inga A, Fronza G, Soussi T. The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. Nucleic Acids Research. 2013; 41(D1): 962–969.
43. Ferreira De Freitas R, Schapira M. A systematic analysis of atomic protein-ligand interactions in the PDB. Med. Chem. Comm., 2017, 8(10), 1970–1981.
44. Wiman KG. Pharmacological reactivation of mutant p53: from protein structure to the cancer patient. Oncogene. 2010; 29 (30): 4245-4252.