Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Phytochemical and Pharmacophoric Fragment Based Anticancer Drug Development

Author(s): S.P. Rochlani*, L.K. Dahiwade and P.B. Choudhari

Volume 17, Issue 1, 2021

Published on: 12 February, 2020

Page: [22 - 31] Pages: 10

DOI: 10.2174/1573409916666200212122445

Price: $65

Abstract

Background: Cancer is the leading cause of death in the current decade. With the advancement in scientific technologies various treatments had been introduced but they suffer from numerous side effects. The root cause of cancer is alteration in the cell cycle which generates cancerous cells. Development of new lead which specifically target cancerous cells is needed to reduce the side effect and to overcome multidrug resistance.

Objective: Design and development of anticancer leads targeting colchicine site of microtubules using structurally screened phytofragments is the primary objective of this work.

Materials and Methods: Bioactive fragments of phytoconstituents were identified from a large dataset of phytochemicals. The identified phytofragments were used to design structures which were screened for virtual interactions with colchicine site of microtubules. Selected set of designed molecules was further screened for drug like properties and toxicity. The designed molecules which surpassed virtual filters were synthesized, characterized and further screened for anticancer potential against HEPG2 liver cancer cell line.

Results: A novel series of chalcones was designed by phytofragment based drug design. Synthesized compounds showed profound anticancer activity comparable to standard, 5-fluoro uracil. In the present communication, rational development of anticancer leads targeting colchicine site of microtubules has been done by integrating pocket modeling and virtual screening with synthesis and biological screening.

Conclusion: In this present work, we found that compounds S4 and S3 showed specific interaction with colchicine site of microtubules and desirable anticancer activity. Further optimization of the lead could yield drug like candidate with reduced side effects and may overcome multidrug resistance.

Keywords: Phytoconstituents, colchicine, microtubules, anticancer, fragment based drug design, chalcone.

« Previous Next »
Graphical Abstract

[1]
Cancer-World Health Organization.. https: www.who.int/news-room/fact-sheets/detail/cancer (Accessed Sept 12 2018)
[2]
Wang, G.; Peng, Z.; Zhang, J.; Qiu, J.; Xie, Z.; Gong, Z. Synthesis, biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site. Bioorg. Chem., 2018, 78, 332-340.
[http://dx.doi.org/10.1016/j.bioorg.2018.03.028]
[3]
Pasquier, E.; Kavallaris, M. Microtubules: a dynamic target in cancer therapy. IUBMB Life, 2008, 60(3), 165-170.
[http://dx.doi.org/10.1002/iub.25] [PMID: 18380008]
[4]
Li, L.; Jiang, S.; Li, X.; Liu, Y.; Su, J.; Chen, J. Recent advances in trimethoxyphenyl(TMP) based tubulin inhibitors targeting the colchicine binding site. Eur. J. Med. Chem., 2018, 10, 482-494.
[http://dx.doi.org/10.1016/j.ejmech.2018.04.011]
[5]
Lin, S.; Hong, T.; Chou, T.; Yang, S.; Chung, W.; Weng, C.; Tsai, M.; Cheng, T.; Jeremy, J.W. 4(1H)-quinolone derivatives overcome acquired resistance to anti-microtubule agents by targeting the colchicine site of β-tubulin. Eur. J. Med. Chem., 2019, 181111584
[6]
Abagyan, R.; Totrov, M. High-throughput docking for lead generation. Curr. Opin. Chem. Biol., 2001, 5(4), 375-382.
[http://dx.doi.org/10.1016/S1367-5931(00)00217-9] [PMID: 11470599]
[7]
Alam, S.; Khan, F. QSAR and docking studies on xanthone derivatives for anticancer activity targeting DNA topoisomerase IIα. Drug Des. Devel. Ther., 2014, 8, 183-195.
[PMID: 24516330]
[8]
Bhatia, M.S.; Ingale, K.B.; Choudhari, P.B.; Bhatia, N.M.; Sawant, R.L. Application quantum and physico chemical molecular descriptors utilizing principal components to study mode of anticoagulant activity of pyridyl chromen-2-one derivatives. Bioorg. Med. Chem., 2009, 17(4), 1654-1662.
[http://dx.doi.org/10.1016/j.bmc.2008.12.055] [PMID: 19157882]
[9]
Ashtekar, S.S.; Bhatia, N.M.; Bhatia, M.S. Exploration of leads from natural domain targeting HER2 in breast cancer: an in-silico approach. Int. J. Pept. Res. Ther., 2018, 25, 659-667.
[http://dx.doi.org/10.1007/s10989-018-9712-y]
[10]
Berman, H.; Henrick, K.; Nakamura, H. Announcing the worldwide Protein Data Bank. Nat. Struct. Biol., 2003, 10(12), 980.
[http://dx.doi.org/10.1038/nsb1203-980] [PMID: 14634627]
[11]
Prota, A.E.; Danel, F.; Bachmann, F.; Bargsten, K.; Buey, R.M.; Pohlmann, J.; Reinelt, S.; Lane, H.; Steinmetz, M.O. The novel microtubule-destabilizing drug BAL27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. J. Mol. Biol., 2014, 426(8), 1848-1860.
[http://dx.doi.org/10.1016/j.jmb.2014.02.005] [PMID: 24530796]
[12]
Khanapure, S.; Jagadale, M.; Bansode, P.; Choudhari, P.; Rashinkar, G. Anticancer activity of ruthenocenyl chalcones and their molecular docking studies. J. Mol. Struct., 2018, 1173(5), 142-147.
[http://dx.doi.org/10.1016/j.molstruc.2018.06.091]
[13]
Zhuang, C.; Zhang, W.; Sheng, C.; Zhang, W.; Xing, C.; Miao, Z. Chalcone: A privileged structure in medicinal chemistry. Chem. Rev., 2017, 117(12), 7762-7810.
[http://dx.doi.org/10.1021/acs.chemrev.7b00020] [PMID: 28488435]
[14]
Singh, P.; Anand, A.; Kumar, V. Recent developments in biological activities of chalcones: a mini review. Eur. J. Med. Chem., 2014, 85, 758-777.
[http://dx.doi.org/10.1016/j.ejmech.2014.08.033] [PMID: 25137491]
[15]
Zhu, C.; Zuo, Y.; Wang, R.; Liang, B.; Yue, X.; Wen, G.; Shang, N.; Huang, L.; Chen, Y.; Du, J.; Bu, X. Discovery of potent cytotoxic ortho-aryl chalcones as new scaffold targeting tubulin and mitosis with affinity-based fluorescence. J. Med. Chem., 2014, 57(15), 6364-6382.
[http://dx.doi.org/10.1021/jm500024v] [PMID: 25061803]
[16]
Wang, Y.; Zhang, H.; Gigant, B.; Yu, Y.; Wu, Y.; Chen, X.; Lai, Q.; Yang, Z.; Chen, Q.; Yang, J. Structures of a diverse set of colchicine binding site inhibitors in complex with tubulin provide a rationale for drug discovery. FEBS J., 2016, 283(1), 102-111.
[http://dx.doi.org/10.1111/febs.13555] [PMID: 26462166]
[17]
Cong, H.; Zhao, X.; Castle, B.T.; Pomeroy, E.J.; Zhou, B.; Lee, J.; Wang, Y.; Bian, T.; Miao, Z.; Zhang, W.; Sham, Y.Y.; Odde, D.J.; Eckfeldt, C.E.; Xing, C.; Zhuang, C. An indole-chalcone inhibits multidrug-resistant cancer cell growth by targeting microtubules. Mol. Pharm., 2018, 15(9), 3892-3900.
[http://dx.doi.org/10.1021/acs.molpharmaceut.8b00359] [PMID: 30048137]
[18]
Wang, G.; Li, C.; He, L.; Lei, K.; Wang, F.; Pu, Y.; Yang, Z.; Cao, D.; Ma, L.; Chen, J.; Sang, Y.; Liang, X.; Xiang, M.; Peng, A.; Wei, Y.; Chen, L. Design, synthesis and biological evaluation of a series of pyrano chalcone derivatives containing indole moiety as novel anti-tubulin agents. Bioorg. Med. Chem., 2014, 22(7), 2060-2079.
[http://dx.doi.org/10.1016/j.bmc.2014.02.028] [PMID: 24629450]
[19]
Vitorović-Todorović, M.D.; Erić-Nikolić, A.; Kolundžija, B.; Hamel, E.; Ristić, S.; Juranić, I.O.; Drakulić, B.J. (E)-4-aryl-4-oxo-2-butenoic acid amides, chalcone-aroylacrylic acid chimeras: design, antiproliferative activity and inhibition of tubulin polymerization. Eur. J. Med. Chem., 2013, 62, 40-50.
[http://dx.doi.org/10.1016/j.ejmech.2013.01.006] [PMID: 23353745]

Rights & Permissions Print Cite
Article Metrics
38
1
© 2024 Bentham Science Publishers | Privacy Policy