Investigation of Paclitaxel Resistant R306C Mutation in β-Tubulin—A Computational Approach

Journal of Cellular Biochemistry
Kanika Verma, K Ramanathan

Abstract

Paclitaxel is the most effective chemotherapeutic agent used for the treatment of a broad spectrum of solid tumors. However, observed paclitaxel resistance in clinical trials presents one of the major obstacles for cancer chemotherapy. Most importantly, resistance due to β-tubulin mutations (R306C) has been intensely debated in recent years. Despite all efforts, mechanism of resistance is still not well understood. In this study, computational techniques were employed to uncover the effect of R306C mutation in the β-tubulin structure and its function. The tools such as I-Mutant, CUPSAT and Fold-X were employed to address the consequence of R306C mutation in the structural stability of β-tubulin. Further, molecular docking and molecular dynamics study was employed to understand the functional impact of β-tubulin mutation. Our results suggest that the R306C mutation causes a significant reduction in the binding affinity between β-tubulin and paclitaxel. Further, docked complex analysis indicates that destruction of conservative hydrogen bond maintained by the residues Arg282 and Gly360 should be responsible for the large conformation changes of the binding pocket in R306C mutant. Finally, molecular dynamics simulations study conf...Continue Reading

References

Jul 17, 1998·Medicinal Research Reviews·A JordanA T McGown
Mar 10, 1999·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·C Dumontet, B I Sikic
Oct 25, 2003·Oncogene·George A OrrSusan Band Horwitz
Mar 9, 2004·The Lancet Oncology·Helen K BerriemanLynn Cawkwell
Jul 1, 2004·Proceedings of the National Academy of Sciences of the United States of America·Thota GaneshDavid G I Kingston
Jul 24, 2004·Acta Crystallographica. Section D, Biological Crystallography·Alexander W Schüttelkopf, Daan M F van Aalten
Nov 3, 2004·Proteins·Kristin L Meagher, Heather A Carlson
Jan 7, 2005·Journal of Medicinal Chemistry·Rino RagnoSilvio Massa
Jun 28, 2005·Nucleic Acids Research·Joost SchymkowitzLuis Serrano
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Feb 24, 2006·FEBS Letters·Howard J FeldmanChristopher W V Hogue
Jul 18, 2006·Nucleic Acids Research·Vijaya ParthibanDietmar Schomburg
Apr 15, 2008·Journal of Molecular Biology·J Torin HuzilDavid C Schriemer
Jul 25, 2009·Journal of Cell Science·Karen E Gascoigne, Stephen S Taylor
Jan 28, 2010·Molecular Cancer Therapeutics·Shanghua YinFernando Cabral
Jun 24, 2011·Journal of Biomolecular Structure & Dynamics·Rituraj PurohitRao Sethumadhavan
Nov 1, 2011·BMC Biology·Jacob D Durrant, J Andrew McCammon
Mar 1, 2012·Bioinformatics·Yingjie LinRoberto Sanchez
Feb 7, 2013·Journal of Biomolecular Structure & Dynamics·Vidya Rajendran, Rao Sethumadhavan
Jun 21, 2013·Journal of Biomolecular Structure & Dynamics·Rituraj Purohit
Apr 25, 2014·International Journal of Molecular Sciences·Asita ElengoeSalehhuddin Hamdan
Jun 22, 2014·Journal of Molecular Modeling·Anish Kumar, K Ramanathan
Mar 1, 2008·Journal of Chemical Theory and Computation·Berk HessErik Lindahl

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Citations

Nov 20, 2016·Journal of Cellular Biochemistry·Ramanathan KaruppasamyShanthi Veerappapillai
Dec 23, 2016·Phytochemical Analysis : PCA·Kanika VermaRamanathan K
Mar 6, 2019·Current Topics in Medicinal Chemistry·Vadim V Tarasov TarasovGjumrakch Aliev
Jan 9, 2021·Journal of Biomolecular Structure & Dynamics·Anica DadwalTulasi Satyanarayana

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