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Volume: 9, Issue: 2, February, 2019
DOI: 10.7324/JAPS.2019.90203



Research Article

In silico predictive for modification of chalcone with pyrazole derivatives as a novel therapeutic compound for targeted breast cancer treatment

Riska Prasetiawati1&3, Adel Zamri2, Melisa Intan Barliana1, Muchtaridi Muchtaridi1

  Author Affiliations


Abstract

One of the most common triggers of breast cancer is over-expression of estrogen receptor alpha (ERα). Long-term therapy of tamoxifen, an ERα antagonist, can reduce patient’s quality of life because of its side effects. In the previous study, 2’,4’-dihydroxy-6-methoxy-3,5-dimethylchalcone (ChalcEA) was isolated as an active compound from the Eugenia aquea leaves that is responsible for breast cancer treatment with positive ERα, however, the potency is lower than tamoxifen. The aim of this study is to find the best-modified chalcone that binds well with the ERα. Drug design approaches used in this study were Structure-Based (Autodock 4.1) and Ligand-Based (LiganScout 4.1). Prediction of absorption, distribution, and toxicity parameters was employed using preADMET and Toxtree. Interactions between tamoxifen and ERα were determined and the differences in the binding modes between tamoxifen and chalcones were observed. Modifina3 had pharmacophore fit score value of 76.42% and the molecular docking studies showed the lowest free energy binding (∆G) of −11.07 kcal/mol while tamoxifen of −10.15 kcal/mol. Modifina3 had absorption and distribution properties with the percentage human intestinal absorption of 95.90%, CaCO2 of 46.95%, and protein plasma binding of 93.55%. Toxicity prediction of Modifina3 was categorized in class III and risk assessment requires compound specific toxicity data. These results suggest that Modifina3 has the potency to be a novel therapeutic compound for potent ERα inhibitor targeted breast cancer.

Keywords:

Chalcone, Modifina3, breast cancer, pharmacophore modeling, molecular docking.



Citation: Prasetiawati R, Zamri A, Barliana MI, Muchtaridi M. In silico predictive for modification of chalcone with pyrazole derivatives as a novel therapeutic compound for targeted breast cancer treatment. J Appl Pharm Sci, 2019; 9(02):020–028.


Copyright: The Author(s). This is an open access article distributed under the Creative Commons Attribution Non-Commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

References

Bentrem, DJ, and Craig Jordan, V. Tamoxifen, raloxifene and the prevention of breast cancer. Minerva Endocrinol, 2002; 27 (2): 127-139.

Bergman, L, Beelen, ML, Gallee, MP, Hollema, H, Benraadt, J, and van Leeuwen, FE. Risk and prognosis of endometrial cancer after tamoxifen for breast cancer. Comprehensive Cancer Centres' ALERT Group. Assessment of Liver and Endometrial cancer Risk following Tamoxifen. Lancet, 2000; 356 (9233): 881-887. https://doi. org/10. 1016/S0140-6736(00)02677-5

Bernstein, L, and Press, MF. Does estrogen receptor expression in normal breast tissue predict breast cancer risk? J Natl Cancer Inst, 1998; 90 (1): 5-7. https://doi. org/10. 1093/jnci/90. 1. 5

Chang, M. Tamoxifen Resistance in Breast Cancer. Biomolecules & Therapeutics, 2012; 20 (3): 256-267. https://doi. org/10. 4062/biomolther. 2012. 20. 3. 256

Cohen, I. Endometrial pathologies associated with postmenopausal tamoxifen treatment. Gynecol Oncol, 2004; 94 (2): 256-266. https://doi. org/10. 1016/j. ygyno. 2004. 03. 048

Cragg, GM, Newman, DJ, and Snader, KM. Natural products in drug discovery and development. J Nat Prod, 1997; 60 (1): 52-60. https://doi. org/10. 1021/np9604893

Davies, C, Pan, H, Godwin, J, Gray, R, Arriagada, R, Raina, V, Abraham, M, Medeiros Alencar, VH, Badran, A, Bonfill, X, Bradbury, J, Clarke, M, Collins, R, Davis, SR, Delmestri, A, Forbes, JF, Haddad, P, Hou, MF, Inbar, M, Khaled, H, Kielanowska, J, Kwan, WH, Mathew, BS, Mittra, I, Muller, B, Nicolucci, A, Peralta, O, Pernas, F, Petruzelka, L, Pienkowski, T, Radhika, R, Rajan, B, Rubach, MT, Tort, S, Urrutia, G, Valentini, M, Wang, Y, and Peto, R. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet, 2013; 381 (9869): 805-816. https://doi. org/10. 1016/S0140-6736(12)61963-1

Dror, O, Shulman-Peleg, A, Nussinov, R, and Wolfson, HJ. Predicting molecular interactions in silico: I. A guide to pharmacophore identification and its applications to drug design. Curr Med Chem, 2004; 11 (1): 71-90. https://doi. org/10. 2174/0929867043456287

Fan, W, Chang, J, and Fu, P. Endocrine therapy resistance in breast cancer: current status, possible mechanisms and overcoming strategies. Future medicinal chemistry, 2015; 7 (12): 1511-1519. https://doi. org/10. 4155/fmc. 15. 93

Ferlay, J, Shin, HR, Bray, F, Forman, D, Mathers, C, and Parkin, DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 2010; 127 (12): 2893-2917. https://doi. org/10. 1002/ijc. 25516

Fisher, B, Costantino, JP, Wickerham, DL, Cecchini, RS, Cronin, WM, Robidoux, A, Bevers, TB, Kavanah, MT, Atkins, JN, Margolese, RG, Runowicz, CD, James, JM, Ford, LG, and Wolmark, N. Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst, 2005; 97 (22): 1652-1662. https://doi. org/10. 1093/jnci/dji372

Fox, EM, Davis, RJ, and Shupnik, MA. ERβ in Breast Cancer – Onlooker, Passive Player, or Active Protector? Steroids, 2008; 73 (11): 1039-1051. https://doi. org/10. 1016/j. steroids. 2008. 04. 006

Gomes, MN, Muratov, EN, Pereira, M, Peixoto, JC, Rosseto, LP, Cravo, PVL, Andrade, CH, and Neves, BJ. Chalcone Derivatives: Promising Starting Points for Drug Design. Molecules, 2017; 22 (8). https://doi. org/10. 3390/molecules22081210

Hawash, MMA, Kahraman, DC, Eren, F, Cetin Atalay, R, and Baytas, SN. Synthesis and biological evaluation of novel pyrazolic chalcone derivatives as novel hepatocellular carcinoma therapeutics. European Journal of Medicinal Chemistry, 2017; 129: 12-26. https://doi. org/10. 1016/j. ejmech. 2017. 02. 002

Ikram, NKK, Durrant, JD, Muchtaridi, M, Zalaludin, AS, Purwitasari, N, Mohamed, N, Rahim, ASA, Lam, CK, Normi, YM, Rahman, NA, Amaro, RE, and Wahab, HA. A Virtual Screening Approach For Identifying Plants with Anti H5N1 Neuraminidase Activity. Journal of Chemical Information and Modeling, 2015; 55 (2): 308-316. https://doi. org/10. 1021/ci500405g

Jandial, DD, Blair, CA, Zhang, S, Krill, LS, Zhang, YB, and Zi, X. Molecular targeted approaches to cancer therapy and prevention using chalcones. Curr Cancer Drug Targets, 2014; 14 (2): 181-200. https://doi. org/10. 2174/1568009614666140122160515

Kalyaanamoorthy, S, and Chen, Y-PP. Structure-based drug design to augment hit discovery. Drug Discovery Today, 2011; 16 (17): 831-839. https://doi. org/10. 1016/j. drudis. 2011. 07. 006

Lahsasni, SA, Al Korbi, FH, and Aljaber, NA. Synthesis, characterization and evaluation of antioxidant activities of some novel chalcones analogues. Chem Cent J, 2014; 8: 32. https://doi. org/10. 1186/1752-153X-8-32

Lee, S, Lee, I, Kim, H, Chang, G, Chung, J, and No, K. The PreADME Approach: Web-based program for rapid prediction of physico-chemical, drug absorption and drug-like properties. Paper read at EuroQSAR 2002 Designing Drugs and Crop Protectants: processes, problems and solutions, 2003, at Massachusetts.

Levin, ER. Integration of the extranuclear and nuclear actions of estrogen. Mol Endocrinol, 2005; 19 (8): 1951-1959. https://doi. org/10. 1210/me. 2004-0390

Morris, GM, Huey, R, Lindstrom, W, Sanner, MF, Belew, RK, Goodsell, DS, and Olson, AJ. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem, 2009; 30 (16): 2785-2791. https://doi. org/10. 1002/jcc. 21256

Muchtaridi, M, Syahidah, H, Subarnas, A, Yusuf, M, Bryant, S, and Langer, T. Molecular Docking and 3D-Pharmacophore Modeling to Study the Interactions of Chalcone Derivatives with Estrogen Receptor Alpha. Pharmaceuticals, 2017; 10 (4): 81. https://doi. org/10. 3390/ph10040081

Muchtaridi, M, Yusuf, M, Diantini, A, Choi, S, Al-Najjar, B, Manurung, J, Subarnas, A, Achmad, T, Wardhani, S, and Wahab, H. Potential Activity of Fevicordin-A from Phaleria macrocarpa (Scheff) Boerl. Seeds as Estrogen Receptor Antagonist Based on Cytotoxicity and Molecular Modelling Studies. International Journal of Molecular Sciences, 2014; 15 (5): 7225. https://doi. org/10. 3390/ijms15057225

Musfiroh, I, Muchtaridi, M, Muhtadi, A, Diantini, A, Hasanah, AN, Udin, LZ, Susilawati, Y, Mustarichie, R, Kartasasmita, RE, and Ibrahim, S. Cytotoxicity Studies of Xanthorrhizol and Its Mechanism Using Molecular Docking Simulation and Pharmacophore Modelling. Journal of Applied Pharmaceutical Science Vol, 2013; 3 (06): 007-015.

Narod, SA. Hormone replacement therapy and the risk of breast cancer. Nat Rev Clin Oncol, 2011; 8 (11): 669-676. https://doi. org/10. 1038/nrclinonc. 2011. 110

Payne, SJ, Bowen, RL, Jones, JL, and Wells, CA. Predictive markers in breast cancer--the present. Histopathology, 2008; 52 (1): 82-90. https://doi. org/10. 1111/j. 1365-2559. 2007. 02897. x

Prasad, YR, Kumar, PR, Deepti, CA, and Ramana, MV. Synthesis and Antimicrobial Activity of Some Novel Chalcones of 2-Hydroxy -1-Acetonapthone and 3-Acetyl Coumarin. E-Journal of Chemistry, 2006; 3 (4). https://doi. org/10. 1155/2006/395386

Rangel, LP, Winter, E, Gauthier, C, Terreux, R, Chiaradia-Delatorre, LD, Mascarello, A, Nunes, RJ, Yunes, RA, Creczynski-Pasa, TB, Macalou, S, Lorendeau, D, Baubichon-Cortay, H, Ferreira-Pereira, A, and Di Pietro, A. New structure-activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity. Drug design, development and therapy, 2013; 7: 1043-1052.

Rojas, K, and Stuckey, A. Breast Cancer Epidemiology and Risk Factors. Clin Obstet Gynecol, 2016; 59 (4): 651-672. https://doi. org/10. 1097/GRF. 0000000000000239

Smyth, MS, and Martin, JHJ. x Ray crystallography. Molecular Pathology, 2000; 53 (1): 8-14. https://doi. org/10. 1136/mp. 53. 1. 8

Subarnas, A, Diantini, A, Abdulah, R, Zuhrotun, A, Hadisaputri, YE, Puspitasari, IM, Yamazaki, C, Kuwano, H, and Koyama, H. Apoptosis induced in MCF-7 human breast cancer cells by 2', 4'-dihydroxy-6-methoxy-3, 5-dimethylchalcone isolated from Eugenia aquea Burm f. leaves. Oncology letters, 2015; 9 (5): 2303-2306. https://doi. org/10. 3892/ol. 2015. 2981

Sun, L, Yang, H, Li, J, Wang, T, Li, W, Liu, G, and Tang, Y. In Silico Prediction of Compounds Binding to Human Plasma Proteins by QSAR Models. ChemMedChem, 2018; 13 (6): 572-581. https://doi. org/10. 1002/cmdc. 201700582

Thomas, S, Brightman, F, Gill, H, Lee, S, and Pufong, B. Simulation Modelling of Human Intestinal Absorption using Caco-2 Permeability and Kinetic Solubility Data for Early Drug Discovery. Journal of Pharmaceutical Sciences, 2008; 97 (10): 4557-4574. https://doi. org/10. 1002/jps. 21305

Wang, Y, Xing, J, Xu, Y, Zhou, N, Peng, J, Xiong, Z, Liu, X, Luo, X, Luo, C, Chen, K, Zheng, M, and Jiang, H. In silico ADME/T modelling for rational drug design. Q Rev Biophys, 2015; 48 (4): 488-515. https://doi. org/10. 1017/S0033583515000190

Wang, Z, Li, Y, Ai, C, and Wang, Y. In silico prediction of estrogen receptor subtype binding affinity and selectivity using statistical methods and molecular docking with 2-arylnaphthalenes and 2-arylquinolines. International journal of molecular sciences, 2010; 11 (9): 3434-3458. https://doi. org/10. 3390/ijms11093434

Wolber, G. Efficient 3D pharmacophore alignment as a tool for structure-based modeling and scoring. Chemistry Central Journal, 2008; 2 (Suppl 1): P49-P49. https://doi. org/10. 1186/1752-153X-2-S1-P49

Wolber, G, and Langer, T. LigandScout: 3-D pharmacophores derived from protein-bound ligands and their use as virtual screening filters. J Chem Inf Model, 2005; 45 (1): 160-169. https://doi. org/10. 1021/ci049885e

Yang, G, Nowsheen, S, Aziz, K, and Georgakilas, AG. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther, 2013; 139 (3): 392-404. https://doi. org/10. 1016/j. pharmthera. 2013. 05. 005

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