In Silico Study of the Interaction and Binding of Tubulin Heterodimer with the Modified Podophyllotoxin Derivatives and Physicochemical Prediction
Abstract
This research had studied the interaction and binding between protein target and anticancer drug derivatives, which are tubulin heterodimer and new podophyllotoxin derivatives (80 ligands). These new derivatives were modified by replacing the functional groups at R1 or R2 positions, by using molecular modeling and molecular docking methods. Physicochemical and ADMET predictions were also considered in order to evaluate the good druglikeness properties for these new podophyllotoxin derivatives, having the most favorable binding with protein target, and having significantly the lowest hepatotoxicity compared to a drug podophyllotoxin. From the calculated results, the new podophyllotoxin derivatives were chosen of 9 ligands (E-binding and Tox_P values), i.e., N11R2 (-7.64 kcal/mol and 1.1), N20R2 (-7.59 kcal/mol and -0.7), N26R2 (-7.48 kcal/mol and 4.4), N25R2 (-7.44 kcal/mol and 4.1), N13R2 (-7.43 kcal/mol and 2.8), N17R2 ( -7.07 kcal/mol and 4.4), N16R1 (-7.04 kcal/mol and 3.2), N9R2 (-7.04 kcal/mol and 3.9) and N40R2 (-7.01 kcal/mol and 3.6), respectively. These new derivatives provided the most specificity to protein target, the more favorable binding with protein target (E-binding £ -7.00 kcal/mol), the good druglikeness properties, and significantly very low hepatotoxicity (-0.7 £ Tox_P £ 4.4) compared to the podophyllotoxin. Moreover, it was also found that the best podophyllotoxin derivatives (9 ligands) were likely to form strong interaction with stable conformations in b-tubulin regions within binding site cavity. From the overall results, it can be concluded that these new podophyllotoxin derivatives might be new drug candidates as the microtubule-depolymerizing agents. Keywords : Podophyllotoxin derivatives ; tubulin heterodimer ; molecular docking ; ADMETReferences
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Etoposide. (2021). Wikipedia The Free Encyclopedia. Retrieved April 15, 2021, from https://en.wikipedia.org /wiki/Etoposide
Gupta, S., Das, L., Datta, A.B., Poddar, A., Janik, M.E., & Bhattacharyya, B. (2006). Oxalone and Lactone Moieties of Podophyllotoxin Exhibit Properties of Both the B and C Rings of Colchicine in Its Binding with Tubulin. Biochemistry, 45, 6467-6475.
Hahn, M. (1995). Receptor surface models: 1. Definition and construction, Journal of Medicinal Chemistry, 38, 2080-2090.
Hu, C., Zhu, X., Wang, G.-H., Wu, X., Han, H.-W., Lu, G.-H., Qi, J.-L., Pang, Y.-J., Yang, R.-W., Wang, X.-M., and Yang, Y.-H. (2018). Design, Synthesis and Anti-cancer Evaluation of Novel Podophyllotoxin Derivatives as Potent Tubulin-Targeting Agents. Medicinal Chemistry Research, 27, 351–365.
Imbert, TF. (1998). Discovery of Podophyllotoxin. Biochimie, 80, 207-222.
Morris, G.M., Huey, R., Lindstrom, W., Sanner, M.F., Belew, R.K., Goodsell, D.S., & Olson, A.J. (2009). Autodock4 and AutoDockTools4: automated docking with selective receptor flexibility. Journal of Computational Chemistry, 30, 2785-2791.
Nerella, S., Kankaka, S. Paidakula, S., & Gavaji, B. (2020). Synthesis of D-ring Modified Acid Hydrazide Derivatives of Podophyllotoxin and Their Anticancer Studies as Tubulin Inhibiting Agents. Bioorganic Chemistry, 94(103384), 1-3.
RCSB Protein Data Bank. (2021). Retrieved April 15, 2021, from https://www.rcsb.org /structure/1SA1
Podophyllotoxin. (2021). Wikipedia The Free Encyclopedia. Retrieved April 15, 2021, from https://en.wikipedia.org
/wiki/Podophyllotoxin
Pongsai, S. (2020). In Silico Drug Design and Molecular Docking Study of Some Related Structural Isomers of Nocodazole Analogues as Tubulin-Polymerization Inhibitors. NU. International Journal of Science, 17(2), 1-16.
Pongsai, S. (2018). In Silico Study of the Interaction between the Modified B-ring Analogues of Colchicine with Tubulin Heterodimer. Burapha Science Journal, 23(1), 44-60.
Pongsai, S., & Duangoe, C. (2013). In Silico Drug Design and Molecular Docking Study of Thalidomide Derivatives as Tubulin-Polymerization Inhibitors. In Proceeding Pure and Applied Chemistry International Conference 2013. (pp. 911-914). Bangsaen Beach: Thailand.
Ravelli, R.B.G., Gigant, B., Curmi, P.A., Jourdain, I., Lachkar, S., Sobel, A., & Marcel Knossow, M. (2004). Insight into Tubulin Regulation from a Complex with Colchicine and a Stathmin-like Domain. Nature, 428, 198-202.
Tenposide. (2021). Wikipedia The Free Encyclopedia. Retrieved April 15, 2021, from https://en.wikipedia.org /wiki/Tenposide
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Published
2022-01-10
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