Docking-based virtual screening of pyrrole containing imatinib structure analogs
https://doi.org/10.29235/1561-8323-2019-63-1-37-43
Abstract
Tyrosine kinase inhibitors became a common treatment option for chronic myelogenous leukemia (CML). Still secondary resistance of patients connected with disease progression remains a major challenge. More effective kinase inhibitors are of great need. In this study, design and molecular docking of combinatory library of de novo imatinib-like structures was performed using Autodock Vina. The main design approach was to replace a benzene linker in the structure of imatinib with a pyrrole ring. Crystal structures of CML-related C-ABL, Human ABL and T315I mutant ABL were used as receptors. Ligands were prepared in MGL Tools. Chimera 1.10 was used for receptor preparation, binding site parametrization and visualization of results. Vina’s exhaustiveness of search was set to 24. All docked structures were filtered based on the known inhibitors results. Two structures showed the promising predicted binding affinities (Autodock Vina’s score -13.6 and -13.1 respectively) comparable with those of approved kinase inhibitors imatinib and nilotinib.
About the Author
A. V. Farina
Institute of Bioorganic Chemistry, National Academy of Sciences of Belarus
Belarus
Belarus
Farina Alexander Vasilievich - Researcher.
5/2, Kuprevich Str., 220141, Minsk
References
1. Milojkovic D., Apperley J. Mechanisms of Resistance to Imatinib and Second-Generation Tyrosine Inhibitors in Chronic Myeloid Leukemia. Clinical Cancer Research, 2009, vol. 15, no. 24, pp. 7519-7527. https://doi.org/10.1158/1078-0432.ccr-09-1068
2. MolView, 2017. Available at: http://molview.org (accessed 25 October 2017).
3. O’Boyle N. M., Banck M., James C. A., Morley C., Vandermeersch T., Hutchison G. R. Open Babel: An open chemical toolbox. Journal of Cheminformatics, 2011, vol. 3, no. 1, pp. 33. https://doi.org/10.1186/1758-2946-3-33
4. Berman H. M., Westbrook J., Zukang F., Gilliland G., Bhat T. N., Weissig H., Shindyalov I. N., Bourne P. E. The Protein Data Bank. Nucleic Acids Research, 2000, vol. 28, no. 1, pp. 235-242. https://doi.org/10.1093/nar/28.L235
5. Nagar B., Bornmann W. G., Pellicena P., Schindler T., Veach D. R., Miller W. T., Clarkson B., Kuriyan J. Crystal structures of the kinase domain of c-Abl in complex with the small molecule inhibitors PD173955 and imatinib (STI-571). Cancer Research, 2002, vol. 62, no. 15, pp. 4236-4243.
6. Weisberg E., Manley P. W., Breitenstein W., Bruggen J., Cowan-Jacob S. W., Ray A., Huntly B., Fabbro D., Fendrich G., Hall-Meyers E., Kung A. L., Mestan J., Daley G. Q., Callahan L., Catley L., Cavazza C., Mohammed A., Neuberg D., Wright R. D., Gilliland D. G., Griffin J. D. Characterization ofAMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell, 2005, vol. 7, no. 2, pp. 129-141. https://doi.org/10.1016/j.ccr.2005.01.007
7. Zhou T., Commodore L., Huang W.-S., Wang Y, Thomas M., Keats J., Xu Q., Rivera V. M., Shakespeare W. C., Clackson T., Dalgarno D. C., Zhu X. Structural Mechanism of the Pan-BCR-ABL Inhibitor Ponatinib (AP24534): Lessons for Overcoming Kinase Inhibitor Resistance. Chemical Biology & Drug Design, 2011, vol. 77, no. 1, pp. 1-11. https://doi.org/10.1111/j.1747-0285.2010.01054.x
8. Trott O., Olson A. J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry, 2010, vol. 31, no. 2, pp. 455-461. https://doi.org/10.1002/jcc.21334
9. Morris G., Huey R., Lindstrom W., Sanner M. F., Belew R. K., Goodsell D. S., Olson A. J. AutoDock4 and AutoDo-ckTools4: Automated docking with selective receptor flexibility. Journal of Computational Chemistry, 2009, vol. 30, no. 16, pp. 2785-2791. https://doi.org/10.1002/jcc.21256
10. Pettersen E., Goddard T. D., Huang C. C., Couch G. S., Greenblatt D. M., Meng E. C., Ferrin T. E. UCSF Chimera. A visualization system for exploratory research and analysis. Journal of Computational Chemistry, 2004, vol. 25, no. 13, pp. 1605-1612. https://doi.org/10.1002/jcc.20084
11. Gozgit J. M., Schrock A., Chen T.-H., Clackson T., Rivera V M. Comprehensive Analysis of the in vitro Potency of Ponatinib, and all other Approved BCR-ABL Tyrosine Kinase Inhibitors (TKIs), Against a Panel of Single and Compound BCR-ABL Mutants. Blood, 2013, vol. 122, no. 21, pp. 3992.
12. FDA Drug Safety Communication: FDA requires multiple new safety measures for leukemia drug Iclusig; company expected to resume marketing. United States Food and Drug Administration. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm379554.htm (accessed 5 October 2017).
Review
Views: 954
Email this article 