Abstract
Podophyllotoxin and its structural derivatives, a class of tubulin polymerization inhibitors, have been the objective of numerous studies to prepare better and safer anti-cancer drugs. A library of podophyllotoxin analogues has been designed consisting of 154 analogues. Their molecular interactions and binding affinities with tubulin protein (1SA1) have been studied using the docking-molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Quantitative structure activity relationships were developed between the cytotoxic activity (pIC50) of these compounds and molecular descriptors like docking score and binding free energy. For both the cases the r 2 was in the range of 0.642–0.728 indicating good data fit and r 2cv was in the range of 0.631–0.719 indicating that the predictive capabilities of the models were acceptable. In addition, a linear correlation was observed between the predicted and experimented pIC50 for the validation data set with correlation coefficient r2 of 0.806 and 0.887, suggesting that the docked structure orientation and the interaction energies are reasonable. Low levels of root mean square error for the majority of inhibitors establish the docking and Prime/MM-GBSA based prediction model as an efficient tool for generating more potent and specific inhibitors of tubulin protein by testing rationally designed lead compounds based on podophyllotoxin derivatization.
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References
Hamel E (1996) Med Res Rev 16:207. doi :10.1002/(SICI)1098-1128(199603)16:2<207::AID-MED4>3.0.CO;2-4
Brewer CF, Loike JD, Horwitz SB, Sternlicht H, Gensler WJ (1979) J Med Chem 22:215. doi:10.1021/jm00189a001
Jardine I, Cassady JM, Douras JD (1980) In: Cassady JM, Douras JD (eds) Anticancer agents based on natural product models. Academic Press, New York
Keller-Juslen C, Kuhn M, von Wartburg A, Stahelin H (1971) J Med Chem 14:936. doi:10.1021/jm00292a012
Weiss SG, Tin-Wa M, Perdue RE Jr, Farnsworth NR (1975) J Pharm Sci 64:95. doi:10.1002/jps.2600640119
Snyder JA, McIntosh RJ (1976) Annu Rev Biochem 45:699. doi:10.1146/annurev.bi.45.070176.003411
Margolis RL, Wilson L (1978) Cell 13:1. doi:10.1016/0092-8674(78)90132-0
Cortese F, Bhattacharyya B, Wolff P (1977) J Biol Chem 252:1134
David-Pfeuty T, Simon C, Pantaloni D (1979) J Biol Chem 21:2392
Lin CM, Hamel E (1981) J Biol Chem 256:9242
Whiting DA (1985) Nat Prod Rep 2:191. doi:10.1039/np9850200191
PJSr Loehrer (1991) Cancer 67:220. doi :10.1002/1097-0142(19910101)67:1+<220::AID-CNCR2820671303>3.0.CO;2-O
Sun L, McPhail AT, Hamel E, Lin CM, Hastie SB, Chang JJ, Lee KH (1993) J Med Chem 36:544. doi:10.1021/jm00057a004
Yamashita A, Tawa R, Imakura Y, Shibuya M, Lee KH (1994) Mol Pharmacol 47:1920
Schrodinger LLC (2007) http://www.schrodinger.com
Polak E, Ribiere G (1969) Revue Francaise Inf Rech Oper, Serie Rouge 16-R1:35
San Feliciano A, Miguel del Corral JM, Gordaliza M, Castro MA (1989) Phytochemistry 28:659. doi:10.1016/0031-9422(89)80081-0
San Feliciano A, Miguel del Corral JM, Gordaliza M, Castro MA (1990) Phytochemistry 29:1335. doi:10.1016/0031-9422(90)85460-W
San Feliciano A, Gordaliza M, Miguel del Corral JM, Castro MA, García-Grávalos MD, Ruiz- Lázaro P (1993) Planta Med 59:246. doi:10.1055/s-2006-959660
Gordaliza M, Castro MA, García-Grávalos MD, Ruiz-Lázaro P, Miguel del Corral JM, San Feliciano A (1994) Arch Pharm (Weinheim) 327:175. doi:10.1002/ardp.19943270309
Castro MA, Gordaliza M, Miguel del Corral JM, San Feliciano A (1994) Org Prep Proced Int 26:539
Gordaliza M, Miguel del Corral JM, Castro MA, López-Vázquez ML, García PA, San Feliciano A, García-Grávalos MD (1995) Bioorg Med Chem Lett 5:2465. doi:10.1016/0960-894X(95)00432-S
Miguel del Corral JM, Gordaliza M, Castro MA, Morales LJ, López JL, San Feliciano A (1995) J Nat Prod 58:870. doi:10.1021/np50120a008
Doré JC, Viel C, Pageot N, Gordaliza M, Castro MA, Miguel del Corral JM, San Feliciano A (1996) J Pharm Belg 51:9
Gordaliza M, Faircloth GT, Castro MA, Miguel del Corral JM, López-Vázquez ML, San Feliciano A (1996) J Med Chem 39:2865. doi:10.1021/jm960023h
Gordaliza M, Castro MA, Miguel del Corral JM, San Feliciano A, Faircloth GT (1997) Bioorg Med Chem Lett 7:2781. doi:10.1016/S0960-894X(97)10072-5
Gordaliza M, Miguel del Corral JM, Castro MA, López-Vázquez ML, San Feliciano A, García Grávalos MD, Carpy A (1995) Bioorg Med Chem 3:1203. doi:10.1016/0968-0896(95)00091-T
Gordaliza M, Castro MA, San Feliciano A, Miguel del Corral JM, López-Vazquez ML, Faircloth GT Patent EP 711765 A1
Miguel del Corral JM, Gordaliza M, Castro MA, García-Grávalos MD, Broughton H, San Feliciano A (1997) Tetrahedron 53:6555. doi:10.1016/S0040-4020(97)00310-4
Hitotsuyanagi Y, Fukuyo M, Tsuda K, Kobayashi M, Ozeki A, Itokawa H, Takeya K (2000) Bioorg Med Chem Lett 10:315. doi:10.1016/S0960-894X(99)00693-9
Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shaw DE, Shelley M, Perry JK, Francis P, Shenkin PS (2004) J Med Chem 47:1739. doi:10.1021/jm0306430
Halgren TA, Murphy RB, Friesner RA, Beard HS, Frye LL, Pollard WT, Banks JL (2004) J Med Chem 47:1750. doi:10.1021/jm030644s
Lyne PD, Lamb ML, Saeh JC (2006) J Med Chem 49:4805. doi:10.1021/jm060522a
Haar ET, Rosenkranz HS, Hamel E, Day BW (1996) Bioorg Med Chem 10:1659
Gordaliza M, Castro MA, Miguel del Corral JM, San Feliciano A (2000) Curr Pharm Des 6:1811. doi:10.2174/1381612003398582
ter Haar E, Rosenkranz HS, Hamel E, Day BW (1996) Bioorg Med Chem 4(10):1659. doi:10.1016/0968-0896(96)00158-7
Loike JD, Brewer CF, Sternlicht H, Gensler WJ, Horwitz SB (1978) Cancer Res 38:2688
San Feliciano A, Miguel del Corral JM, Gordaliza M, Castro MA (1991) Phytochemistry 30:3483. doi:10.1016/0031-9422(91)83240-L
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Afroz Alam, M., Naik, P.K. Molecular modelling evaluation of the cytotoxic activity of podophyllotoxin analogues. J Comput Aided Mol Des 23, 209–225 (2009). https://doi.org/10.1007/s10822-008-9252-1
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DOI: https://doi.org/10.1007/s10822-008-9252-1