Search for Novel Antagonist/S of HIF-1α from Selected Synthetic Analgesics/ Bioactive Flavonoids: An In-Silico Approach
Pharmaceutical Science-Drug Design and Development
DOI:
https://doi.org/10.22376/ijlpr.2023.13.6.P12-P27Keywords:
Breast Cancer Metastasis, HIF-1α, Synthetic drugs, Flavonoids, Analgesics, Molecular Docking, PharmacokineticsAbstract
Computer aided drug designing as well as drug repurposing implies the usage of molecular modelling techniques like analysis of the structures of receptor and ligand, molecular docking, pharmacokinetics and toxicity prediction, to explain the bioactivity of the synthetic molecules or plant secondary metabolites to design more efficient drug candidates or to repurpose an old drug in new diseases. Numerous studies have demonstrated that the low oxygen environment inside the cell is a key factor in developing breast cancer metastasis. To gain insight into the spread of breast cancer, hypoxia-inducible factor 1 (HIF-1), one of the master regulators of the hypoxic response, has been intensively explored. Our current research focuses on the insilico analysis and comparative study to evaluate the effects of different cancer drugs, analgesics, and plant-derived flavonoid compounds on HIF-1α regulation of breast cancer metastasis. According to the study, Quercetin shows the maximum binding affinity, i.e., -8.2 kcal/ mol. followed by Letrozole (-7.3 kcal/mol.), Naringenin (-7.11 kcal/mol), Tamoxifen (-7.07 kcal/mol), Phenacetin (-6.16 kcal/mol), and Aspirin (-5.7 kcal/mol). The study highlighted that Quercetin has the strongest binding affinity whereas Aspirin has the least binding affinity with HIF-1α protein. Hence the least toxic compound Quercetin can be a good candidate to control breast cancer metastasis by modulating the HIF-1 pathway.
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90. doi: 10.3322/caac.20107, PMID 21296855.
Lech R, Przemysław O. Epidemiological models for breast cancer risk estimation. Ginekol Pol. 2011;82(6):451-4. PMID 21853936.
Semenza GL. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol Sci. 2012;33(4):207-14. doi: 10.1016/j.tips.2012.01.005, PMID 22398146.
Semenza GL. Oxygen sensing, homeostasis, and disease reply. N Engl J Med. 2011;365(19):537-47.
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, et al. The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol. 2000;157(2):411-21. doi: 10.1016/s0002-9440(10)64554-3, PMID 10934146.
Zhong H, de Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res. 1999;59(22):5830-5. PMID 10582706.
Zhong H, Chiles K, Feldser D, Laughner E, Hanrahan C, Georgescu MM, et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT / FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics. Cancer Res. 2000;60(6):1541-5. PMID 10749120.
Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 2008;18(1):27-34. doi 10.1016/j.gde.2007.12.006, PMID 18282701.
Chaturvedi P, Gilkes DM, Wong CC, Kshitiz, Luo W, Zhang H, et al. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest. 2013;123(1):189-205. doi: 10.1172/JCI64993, PMID 23318994.
Wang GL, Jiang BH, Rue EA, Semenza GL. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci U S A. 1995;92(12):5510-4. doi 10.1073/pans.92.12.5510, PMID 7539918.
Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3(10):721-32. doi: 10.1038/nrc1187, PMID 13130303.
Bos R, van der Groep P, Greijer AE, Shvarts A, Meijer S, Pinedo HM, et al. Hypoxia-inducible factor-1α independently predicts prognosis in patients with lymph node-negative breast carcinoma. Cancer. 2003;97(6):1573-81. doi: 10.1002/cncr.11246, PMID 12627523.
Steeg PS. Tumor metastasis: mechanistic insights and clinical challenges. Nat Med. 2006;12(8):895-904. doi 10.1038/nm1469, PMID 16892035.
Shahbaz K, Mehfooz A, Khadam W, Din MU, Shahbaz K, et al. Breast cancer vaccination- an envisioned future. IAJPR. 2014;4(3):1580-5.
Hanif M, Zaidi P, Kamal S, Hameed A. Institution-based cancer incidence in a local population in Pakistan: nine-year data analysis. Asian Pac J Cancer Prev. 2009;10(2):227-30. PMID 19537889.
Guelen PJ, Stevenson D, Briggs RJ, De Vos D. The bioavailability of Tamoplex (Tamoxifen). Part 2. A single dose cross-over study in healthy male volunteers. Methods Find Exp Clin Pharmacol. 1987;9(10):685-90. PMID 3441162.
Fuchs WS, Leary WP, van der Meer MJ, Gay S, Witschital K, von Nieciecki A MMJ, et al. Pharmacokinetics and bioavailability of Tamoxifen in healthy postmenopausal women. Arzneimittelforschung. 1996;46(4):418-22. PMID 8740091.
Chen JH, Chang YC, Chang D, Wang YT, Nie K, Chang RF et al.. Reduction of breast density following tamoxifen treatment evaluated by 3-D MRI: a preliminary study. Magn Reson Imaging. 2011;29(1):91-8. doi: 10.1016/j.mri.2010.07.009. PMID 20832226.
Haynes BP, Dowsett M, Miller WR, Dixon JM, Bhatnagar AS. The pharmacology of letrozole. J Steroid Biochem Mol Biol. 2003;87(1):35-45. doi: 10.1016/s0960-0760(03)00384-4, PMID 14630089.
Lang M, Batzl C, Furet P, Bowman R, Häusler A, Bhatnagar AS. Structure-activity relationships and binding model of novel aromatase inhibitors. J Steroid Biochem Mol Biol. 1993;44(4-6):421-8. doi: 10.1016/0960-0760(93)90245-r, PMID 8476755.
Bhatnagar AS, Brodie AMH, Long BJ, Evans DB, Miller WR. Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors. J Steroid Biochem Mol Biol. 2001;76(1-5):199-202. doi: 10.1016/s0960-0760(01)00050-4, PMID 11384878.
Sioufi A, Sandrenan N, Godbillon J, Trunet P, Czendlik C, Howald H et al. Comparative bioavailability of letrozole under fed and fasting conditions in 12 healthy subjects after a 2.5 mg single oral administration. Biopharm Drug Dispos. 1997b;18(6):489-97. doi: 10.1002/(sici)1099-081x(199708)18:6<489::aid-bdd36>3.0.co;2-p, PMID 9267682.
Harris RE, Beebe-Donk J, Doss H, Burr Doss DB. Aspirin, ibuprofen, and other non-steroidal anti-inflammatory drugs in cancer prevention: a critical review of non-selective COX-2 blockade (review) [review]. Oncol Rep. 2005;13(4):559-83. doi: 10.3892/or.13.4.559, PMID 15756426.
Kaiser J. Will an aspirin a day keep cancer away? Science. 2012;337(6101):1471-3. doi 10.1126/science.337.6101.1471, PMID 22997320.
Ferrández A, Piazuelo E, Castells A. Aspirin and the prevention of colorectal cancer. Best Pract Res Clin Gastroenterol. 2012;26(2):185-95. doi: 10.1016/j.bpg.2012.01.009, PMID 22542156.
Sawaoka H, Tsuji S, Tsujii M, Gunawan ES, Sasaki Y, Kawano S et al. Cyclooxygenase inhibitors suppress angiogenesis and reduce tumor growth in vivo. Lab Invest. 1999;79(12):1469-77. PMID 10616198.
Chan TA, Morin PJ, Vogelstein B, Kinzler KW. Mechanisms underlying nonsteroidal antiinflammatory drug-mediated apoptosis. Proc Natl Acad Sci U S A. 1998;95(2):681-6. doi 10.1073/pans.95.2.681, PMID 9435252.
Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302(6):649-58. doi 10.1001/jama.2009.1112, PMID 19671906.
Xu XM, Sansores-Garcia L, Chen XM, Matijevic-Aleksic N, Du M, Wu KK. Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci U S A. 1999;96(9):5292-7. doi 10.1073/pans.96.9.5292, PMID 10220459.
Gault MH, Shahidi NT, Gabe A. The effect of acetylsalicylic acid, caffeine, and codeine on the excretion of phenacetin metabolites. Can J Physiol Pharmacol. 1972;50(8):809-16. doi: 10.1139/y72-117, PMID 5053793.
Nabavi SM, Šamec D, Tomczyk M, Milella L, Russo D, Habtemariam S, et al. Flavonoid biosynthetic pathways in plants: versatile targets for metabolic engineering. Biotechnol Adv. 2020;38:107316. doi 10.1016/j.biotechadv.2018.11.005, PMID 30458225.
Kofink M, Papagiannopoulos M, Galensa R. (-)-Catechin in cocoa and chocolate: occurrence and analysis of an atypical flavan-3-ol enantiomer. Molecules. 2007;12(7):1274-88. doi: 10.3390/12071274, PMID 17909484.
Panache AN, Diwan AD, Chandra SR. Flavonoids: an overview. J Nutr Sci. 2016;5:e47. doi: 10.1017/jns.2016.41. PMID 28620474.
Varghese E, Samuel SM, Abotaleb M, Cheema S, Mamtani R, Büsselberg D. The ”yin and yang” of natural compounds in anticancer therapy of triple-negative breast cancers. Cancers. 2018;10(10):346. doi: 10.3390/cancers10100346, PMID 30248941.
Liu RH. Nutrition, and potential cancer synergy of phytochemicals in cancer prevention: mechanism of action 1. Int Res Conf. Food Nutr Cancer Potential. Vol. 134; 2004. p. 3479-85.
De Groot H, Rauen U. Tissue injury by reactive oxygen species and the protective effects of flavonoids. Fundam Clin Pharmacol. 1998;12(3):249-55. doi: 10.1111/j.1472-8206.1998.tb00951.x, PMID 9646056.
Middleton EJ. Effect of plant flavonoids on immune and inflammatory cell functions. Adv Exp Med Biol. 1998;439:175-82. doi: 10.1007/978-1-4615-5335-9_13, PMID 9781303.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983-88. doi 10.1073/pans.0530291100, PMID 12629218.
Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: a novel approach for breast cancer therapy. Semin Cancer Biol. 2016;40-41:192-208. doi: 10.1016/j.semcancer.2016.09.001, PMID 27609747.
Lv L, Liu C, Chen C, Yu X, Chen G, Shi Y, et al. Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer. Oncotarget. 2016;7(22):32184-99. doi: 10.18632/oncotarget.8607, PMID 27058756.
Krause M, Galensa R. Bestimmung von Naringenin und Naringenin-Chalkon in Tomatenschalen mit RP-HPLC nach Festphasenextraktion. Z Lebensm Unters Forch. 1992;194(1):29-32. doi: 10.1007/BF01191036.
Masjedi A, Hashemi V, Hojjat-Farsangi M, Ghalamfarsa G, Azizi G, Yousefi M et al. The significant role of interleukin-6 and its signaling pathway in the immunopathogenesis and treatment of breast cancer. Biomed Pharmacother. 2018;108:1415-24. doi 10.1016/j.biopha.2018.09.177, PMID 30372844.
Wang R, Wang J, Dong T, Shen J, Gao X, Zhou J. Naringenin has a chemoprotective effect in MDA-MB-231 breast cancer cells by inhibiting caspase-3 and −9 activities. Oncol Lett. 2019;17(1):1217-22. doi: 10.3892/ol.2018.9704, PMID 30655887.
Cella D, Fallowfield LJ. Recognition and management of treatment-related side effects for breast cancer patients receiving adjuvant endocrine therapy. Breast Cancer Res Treat. 2008;107(2):167-80. doi: 10.1007/s10549-007-9548-1, PMID 17876703.
Kanno S-I, Tomizawa A, Hiura T, Osanai Y, Shouji A, Ujibe M, et al. Inhibitory effects of Naringenin on tumor growth in human cancer cell lines and sarcoma S-180-implanted mice. Biol Pharm Bull. 2005;28(3):527-30. doi: 10.1248/bpb.28.527, PMID 15744083.
Bulzomi P, Bolli A, Galluzzo P, Acconcia F, Ascenzi P, Marino M. The naringenin-induced proapoptotic effect in breast cancer cell lines holds out against a high bisphenol A background. IUBMB Life. 2012;64(8):690-6. doi 10.1002/tub.1049, PMID 22692793.
Rezaei-Seresht H, Cheshomi H, Falanji F, Movahedi-Motlagh F, Hashemian M, Mireskandari E. Cytotoxic activity of caffeic acid and gallic acid against MCF-7 human breast cancer cells: an in silico and in vitro study. Avicenna J Phytomed. 2019;9(6):574-86. doi 10.22038/AJP.2019.13475, PMID 31763216.
BIOVIA, Dassault systèmes, [Discovery Studio client]; 2020.
Colovos C, Yeates TO. Verification of protein structures: patterns of nonbonded atomic interactions. Protein Sci. 1993;2(9):1511-9. doi: 10.1002/pro.5560020916, PMID 8401235.
De Oliveira CCS, Pereira GRC, De Alcantara JYS, Antunes D, Caffarena ER, De Mesquita JF. In silico analysis of the V66M variant of human BDNF in psychiatric disorders: an approach to precision medicine. PLOS ONE. 2019;14(4):e0215508. doi: 10.1371/journal.pone.0215508, PMID 30998730.
Laskowski RA, MacArthur MW, Moss DS, Thornton JM. PROCHECK: A program to check the stereochemical quality of protein structures. J Appl Crystallogr. 1993;26(2):283-91. doi: 10.1107/S0021889892009944.
Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R et al. SWISS-MODEL: homology modeling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-303. doi: 10.1093/nar/gky427, PMID 29788355.
Wiederstein M, Sippl MJ. ProSA-web: interactive web service for recognizing errors in three-dimensional structures of proteins. Nucleic Acids Res. 2007;35(Web Server issue):W407-10. doi: 10.1093/nar/gkm290, PMID 17517781.
Daina A, Michielin O, Zoete V. SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Sci Rep. 2017;7:42717. doi: 10.1038/srep42717, PMID 28256516.
Pratap Singh HP, Sharma CS, Mishra SS, Pandiya H, Kumar N. In silico ADME, Bioactivity and Toxicity Prediction of Some Selected anti-Parkinson Agents. Int J Pharm Phytopharmacol Res. 2017;6(3):64-7. doi: 10.24896/eijppr.2016631.
Cunha EL, Santos CF, Braga FS, Costa JS, Silva RC, Favacho HAS et al. Computational Investigation of Antifungal Compounds Using Molecular Modeling and Prediction of ADME/Tox Properties. J Comp Theor Nanosci. 2015;12(10):3682-91. doi: 10.1166/jctn.2015.4260.
Bruce NA, Gurney EG, James AM, Bartsch H. Carcinogens as frameshift Mutagens: metabolites and Derivatives of 2-acetylaminofluorene and another aromatic amine Carcinogens. PNAS. 1973;69:3128-213.
Verma A. Lead finding from Phyllanthus debris with hepatoprotective potentials. Asian Pac J Trop Biomed. 2012;2(3):S1735-7. doi: 10.1016/S2221-1691(12)60486-9.
O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: an open chemical toolbox. J Cheminform. 2011;3:33. doi: 10.1186/1758-2946-3-33, PMID 21982300.
Rehan M. Shafiullah. Medicinal plant-based saponins are targeting COVID-19 Mpro in-silico. Tradit Med Res. 2021;24.
Binkowski TA, Naghibzadeh S, Liang J. CASTp: computed Atlas of Surface Topography of proteins. Nucleic Acids Res. 2003;31(13):3352-5. doi: 10.1093/nar/gkg512, PMID 12824325.
Kuriata A, Gierut AM, Oleniecki T, Ciemny MP, Kolinski A, Kurcinski M et al. CABS-flex 2.0: a web server for fast simulations of the flexibility of protein structures. Nucleic Acids Res. 2018;46(W1):W338-43. doi: 10.1093/nar/gky356, PMID 29762700.
Marrink SJ, Risselada HJ, Yefimov S, Tieleman DP, de Vries AH. The MARTINI force field: a coarse-grained model for biomolecular simulations. J Phys Chem B. 2007;111(27):7812-24. doi: 10.1021/jp071097f, PMID 17569554.
Dosztányi Z, Mészáros B, Simon I. Bioinformatical approaches to characterize intrinsically disordered/unstructured proteins. Brief Bioinform. 2010;11(2):225-43. doi 10.1093/bib/bbp061, PMID 20007729.
Jamroz M, Kolinski A, Kmiecik S. CABS-flex: server for fast simulation of protein structure fluctuations. Nucleic Acids Res. 2013;41(Web Server issue):W427-31. doi: 10.1093/nar/gkt332, PMID 23658222.
Srimai V, Ramesh M, Satya Parameshwar KS, Parthasarathy T. Computer-aided design of selective cytochrome P450 inhibitors and docking studies of alkyl resorcinol derivatives. Med Chem Res. 2013;22(11):5314-23. doi: 10.1007/s00044-013-0532-5.
Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46(1-3):3-26. doi: 10.1016/s0169-409x(00)00129-0. PMID 11259830.
Veber DF, Johnson SR, Cheng HY, Smith BR, Ward KW, Kopple KD. Molecular properties that influence the oral bioavailability of drug candidates. J Med Chem. 2002;45(12):2615-23. doi: 10.1021/jm020017n, PMID 12036371.
Muegge I, Heald SL, Brittelli D. Simple selection criteria for the drug-like chemical matter. J Med Chem. 2001;44(12):1841-6. doi: 10.1021/jm015507e, PMID 11384230.
Arnott JA, Planey SL. The influence of lipophilicity in drug discovery and design. Expert Opin Drug Discov. 2012;7(10):863-75. doi: 10.1517/17460441.2012.714363, PMID 22992175.
Kerns EH, Di L. Pharmaceutical profiling in drug discovery. Drug Discov Today. 2003;8(7):316-23. doi: 10.1016/s1359-6446(03)02649-7, PMID 12654544.
Stegemann S, Leveiller F, Franchi D, De Jong H, Lindén H. When poor solubility becomes an issue: from early stage to proof of concept. Eur J Pharm Sci. 2007;31(5):249-61. doi: 10.1016/j.ejps.2007.05.110, PMID 17616376.
Borra NK, Kuna Y. Evolution of toxic properties of antialzheimer’s drugs through Lipinski’s rule of five. Int J Pure App Biosci. 2013;1:28-36.
Wang Y, Xing J, Xu Y, Zhou N, Peng J, Xiong Z et al. In silico ADME/T modeling for rational drug design. Q Rev Biophys. 2015;48(4):488-515. doi: 10.1017/S0033583515000190, PMID 26328949.
Khan MF, Bari MA, Islam MK, Islam MS, Kayser MS, Nahar N et al. The natural antitubercular agents: in silico study of physicochemical, pharmacokinetic, and toxicological properties. J Appl Pharm Sci. 2017;7:034-8.
Shekhar Mishra SS, Sharma CS, Singh HP, Pandiya H, Kumar N. In silico ADME, Bioactivity and Toxicity Parameters Calculation of Some Selected Anti-Tubercular Drugs. Int J Pharm Phytopharmacol Res. 2016;6(6):77-9. doi: 10.24896/eijppr.2016661.
Yu HB, Zou BY, Wang XL, Li M. Investigation of miscellaneous hERG inhibition in the large, diverse compound collection using automated patch-clamp assay. Acta Pharmacol Sin. 2016;37(1):111-23. doi 10.1038/aps.2015.143, PMID 26725739.
Singh S, Gupta AK, Verma A. Molecular properties and bioactivity score of the Aloe vera antioxidant compounds-in order to lead finding. Res J Pharm Biol Chem Sci. 2013;4:876-81.
Published
How to Cite
Issue
Section
Copyright (c) 2023 Moumita Saha, Rumana Rahman, Anisha Mukherjee, Chandreyi Ghosh, Sirshendu Chatterjee
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
