Abstract
Potential drug target identification and mechanism of action is an important step in drug discovery process, which can be achieved by biochemical methods, genetic interactions or computational conjectures. Sometimes more than one approach is implemented to mine out the potential drug target and characterize the on-target or off-target effects. A novel anticancer agent RH1 is designed as pro-drug to be activated by NQO1, an enzyme overexpressed in many types of tumors. However, increasing data show that RH1 can affect cells in NQO1-independent fashion. Here, we implemented the bioinformatics approach of modeling and molecular docking for search of RH1 targets among protein kinase species. We have examined 129 protein kinases in total where 96 protein kinases are in complexes with their inhibitor, 11 kinases were in the unbound state with any ligand and for 22 protein kinases 3D structure were modeled. Comparison of calculated free energy of binding of RH1 with indigenous kinase inhibitors binding efficiency as well as alignment of their pharmacophoric maps let us predict and ranked protein kinases such as KIT, CDK2, CDK6, MAPK1, NEK2 and others as the most prominent off-targets of RH1. Our finding opens new avenues in search of protein targets that might be responsible for curing cancer by new promising drug RH1 in NQO1-independent way.
Similar content being viewed by others
References
Schenone M, Dančík V, Wagner BK, Clemons PA. Target identification and mechanism of action in chemical biology and drug discovery. Nat Chem Biol. 2013;9:232–40. doi:10.1038/nchembio.1199.
Rasolohery I, Moroy G, Guyon F. PatchSearch: a fast computational method for off-target detection. J Chem Inf Model. 2017;57:769–77. doi:10.1021/acs.jcim.6b00529.
Bunnage ME. Getting pharmaceutical R&D back on target. Nat Chem Biol. 2011;7:335–9. doi:10.1038/nchembio.581.
Merino A, Bronowska AK, Jackson DB, Cahill DJ. Drug profiling: knowing where it hits. Drug Discov Today. 2010;15:749–56. doi:10.1016/j.drudis.2010.06.006.
Lavecchia A, Cerchia C. In silico methods to address polypharmacology: current status, applications and future perspectives. Drug Discov Today. 2016;21:288–98. doi:10.1016/j.drudis.2015.12.007.
Klaeger S, Gohlke B, Perrin J, Gupta V, Heinzlmeir S, Helm D, et al. Chemical proteomics reveals ferrochelatase as a common off-target of kinase inhibitors. ACS Chem Biol. 2016;11:1245–54. doi:10.1021/acschembio.5b01063.
Cohen P. Protein kinases? The major drug targets of the twenty-first century? Nat Rev Drug Discov. 2002;1:309–15. doi:10.1038/nrd773.
Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002;298:1912–34. doi:10.1126/science.1075762.
Cohen P, Alessi DR. Kinase drug discovery—Wnext in the field? ACS Chem Biol. 2013;8:96–104. doi:10.1021/cb300610s.
Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015;36:422–39. doi:10.1016/j.tips.2015.04.005.
Ward TH, Danson S, McGown AT, Ranson M, Coe NA, Jayson GC, et al. Preclinical evaluation of the pharmacodynamic properties of 2,5-diaziridinyl-3-hydroxymethyl-6-methyl-1,4-benzoquinone. Clin Cancer Res. 2005;11:2695–701. doi:10.1158/1078-0432.CCR-04-1751.
Dehn DL, Inayat-Hussain SH, Ross D. RH1 induces cellular damage in an NAD(P)H: Quinone oxidoreductase 1-dependent manner: relationship between DNA cross-linking, cell cycle perturbations, and apoptosis. J Pharmacol Exp Ther. 2004;313:771–9. doi:10.1124/jpet.104.081380.
Danson SJ, Johnson P, Ward TH, Dawson M, Denneny O, Dickinson G, et al. Phase I pharmacokinetic and pharmacodynamic study of the bioreductive drug RH1. Ann Oncol. 2011;22:1653–60. doi:10.1093/annonc/mdq638.
Parkinson EI, Bair JS, Cismesia M, Hergenrother PJ. Efficient NQO1 substrates are potent and selective anticancer agents. ACS Chem Biol. 2013;8:2173–83. doi:10.1021/cb4005832.
Tudor G, Alley M, Nelson CM, Huang R, Covell DG, Gutierrez P, et al. Cytotoxicity of RH1: NAD(P)H:quinone acceptor oxidoreductase (NQO1)-independent oxidative stress and apoptosis induction. Anticancer Drugs. 2005;16:381–91.
Leung KKK, Shilton BH. Quinone reductase 2 is an adventitious target of protein kinase CK2 inhibitors TBBz (TBI) and DMAT. Biochemistry. 2015;54:47–59. doi:10.1021/bi500959t.
Winger JA, Hantschel O, Superti-Furga G, Kuriyan J. The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2). BMC Struct Biol. 2009;9:7. doi:10.1186/1472-6807-9-7.
Rix U, Hantschel O, Dürnberger G, Remsing Rix LL, Planyavsky M, Fernbach NV, et al. Chemical proteomic profiles of the BCR-ABL inhibitors imatinib, nilotinib, and dasatinib reveal novel kinase and nonkinase targets. Blood. 2007;110:4055–63. doi:10.1182/blood-2007-07-102061.
Bantscheff M, Eberhard D, Abraham Y, Bastuck S, Boesche M, Hobson S, et al. Quantitative chemical proteomics reveals mechanisms of action of clinical ABL kinase inhibitors. Nat Biotechnol. 2007;25:1035–44. doi:10.1038/nbt1328.
Chen J, Bardes EE, Aronow BJ, Jegga AG. ToppGene suite for gene list enrichment analysis and candidate gene prioritization. Nucl Acids Res. 2009;37:W305–11. doi:10.1093/nar/gkp427.
Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 2003;13:2129–41. doi:10.1101/gr.772403.
Mi H, Muruganujan A, Thomas PD. PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucl Acids Res. 2013;41(2013):D377–86. doi:10.1093/nar/gks1118.
Selleckchem. 2017. http://www.selleckchem.com/.
Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, et al. The protein data bank. Nucl Acids Res. 2000;28:235–42.
Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem substance and compound databases. Nucl Acids Res. 2016;44:D1202–13. doi:10.1093/nar/gkv951.
Law V, Knox C, Djoumbou Y, Jewison T, Guo AC, Liu Y, et al. DrugBank 4.0: shedding new light on drug metabolism. Nucl Acids Res. 2014;42:D1091–7. doi:10.1093/nar/gkt1068.
Irwin JJ, Sterling T, Mysinger MM, Bolstad ES, Coleman RG. ZINC: a free tool to discover chemistry for biology. J Chem Inf Model. 2012;52:1757–68. doi:10.1021/ci3001277.
Rappe AK, Casewit CJ, Colwell KS, Goddard WA, Skiff WM. UFF, a full periodic table force field for molecular mechanics and molecular dynamics simulations. J Am Chem Soc. 1992;114:10024–35. doi:10.1021/ja00051a040.
Sievers F, Wilm A, Dineen D, Gibson TJ, Karplus K, Li W, et al. Fast, scalable generation of high-quality protein multiple sequence alignments using clustal omega. Mol Syst Biol. 2011;7:539. doi:10.1038/msb.2011.75.
Garnier J, Gibrat J.-F, Robson B. GOR method for predicting protein secondary structure from amino acid sequence. Methods Enzymol. 1996;266:540–53. doi:10.1016/S0076-6879(96)66034-0.
Biasini M, Bienert S, Waterhouse A, Arnold K, Studer G, Schmidt T, et al. SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucl Acids Res. 2014;42:W252–8. doi:10.1093/nar/gku340.
Kelley LA, Mezulis S, Yates CM, Wass MN, Sternberg MJE. The Phyre2 web portal for protein modeling, prediction and analysis. Nat Protoc. 2015;10:845–58. doi:10.1038/nprot.2015.053.
Yang J, Yan R, Roy A, Xu D, Poisson J, Zhang Y. The I-TASSER Suite: protein structure and function prediction. Nat Methods. 2014;12:7–8. doi:10.1038/nmeth.3213.
Wiederstein M, Sippl MJ. ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins. Nucl Acids Res. 2007;35:W407–10. doi:10.1093/nar/gkm290.
Lovell SC, Davis IW, Arendall WB, de Bakker PIW, Word JM, Prisant MG, et al. Structure validation by Cα geometry: ϕ,ψ and Cβ deviation. Proteins Struct Funct Bioinform. 2003;50:437–50. doi:10.1002/prot.10286.
Phillips JC, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E, et al. Scalable molecular dynamics with NAMD. J Comput Chem. 2005;26:1781–802. doi:10.1002/jcc.20289.
Humphrey W, Dalke A, Schulten K. VMD: visual molecular dynamics. J Mol Graph. 1996;14(33–8):27–8.
Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30:2785–91. doi:10.1002/jcc.21256.
Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31:455–61. doi:10.1002/jcc.21334.
Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera? A visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–12. doi:10.1002/jcc.20084.
Dassault Systèmes BIOVIA. Discovery Studio Modeling Environment. 2017. http://accelrys.com/products/collaborative-science/biovia-discovery-studio/.
Schrödinger L. The PyMOL molecular graphics system. 2017. https://www.schrodinger.com/pymol.
Huang D, Zhou T, Lafleur K, Nevado C, Caflisch A. Kinase selectivity potential for inhibitors targeting the ATP binding site: a network analysis. Bioinformatics. 2010;26:198–204. doi:10.1093/bioinformatics/btp650.
Peng S-B, Henry JR, Kaufman MD, Lu W-P, Smith BD, Vogeti S, et al. Inhibition of RAF isoforms and active dimers by LY3009120 Leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell. 2015;28:384–98. doi:10.1016/j.ccell.2015.08.002.
Zhao B. Structural basis for Chk1 inhibition by UCN-01. J Biol Chem. 2002;277:46609–15. doi:10.1074/jbc.M201233200.
Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U. Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem. 2005;48:737–43. doi:10.1021/jm049353p.
Bösken CA, Farnung L, Hintermair C, Merzel Schachter M, Vogel-Bachmayr K, Blazek D, et al. The structure and substrate specificity of human Cdk12/cyclin K. Nat Commun. 2014;5:3505. doi:10.1038/ncomms4505.
Mol CD, Lim KB, Sridhar V, Zou H, Chien EYT, Sang B-C, et al. Structure of a c-kit product complex reveals the basis for kinase transactivation. J Biol Chem. 2003;278:31461–4. doi:10.1074/jbc.C300186200.
Yap JL, Worlikar S, MacKerell AD, Shapiro P, Fletcher S. Small-molecule inhibitors of the ERK signaling pathway: towards novel anticancer therapeutics. ChemMedChem. 2011;6:38–48. doi:10.1002/cmdc.201000354.
Duncia JV, Santella JB, Higley CA, Pitts WJ, Wityak J, Frietze WE, et al. MEK inhibitors: the chemistry and biological activity of U0126, its analogs, and cyclization products. Bioorg Med Chem Lett. 1998;8:2839–44.
Unzue A, Dong J, Lafleur K, Zhao H, Frugier E, Caflisch A, et al. Pyrrolo[3,2- b]quinoxaline derivatives as types I 1/2 and II Eph tyrosine kinase inhibitors: structure-based design, synthesis, and in vivo validation. J Med Chem. 2014;57:6834–44. doi:10.1021/jm5009242.
Kiryanov A, Natala S, Jones B, McBride C, Feher V, Lam B, et al. Structure-based design and SAR development of 5,6-dihydroimidazolo[1,5-f]pteridine derivatives as novel Polo-like kinase-1 inhibitors. Bioorg Med Chem Lett. 2017;27:1311–5. doi:10.1016/j.bmcl.2016.10.009.
Nie Z, Feher V, Natala S, McBride C, Kiryanov A, Jones B, et al. Discovery of TAK-960: an orally available small molecule inhibitor of polo-like kinase 1 (PLK1). Bioorg Med Chem Lett. 2013;23:3662–6. doi:10.1016/j.bmcl.2013.02.083.
Duffey MO, Vos TJ, Adams R, Alley J, Anthony J, Barrett C, et al. Discovery of a potent and orally bioavailable benzolactam-derived inhibitor of polo-like kinase 1 (MLN0905). J Med Chem. 2012;55:197–208. doi:10.1021/jm2011172.
Jain R, Mathur M, Lan J, Costales A, Atallah G, Ramurthy S, et al. Discovery of potent and selective RSK inhibitors as biological probes. J Med Chem. 2015;58:6766–83. doi:10.1021/acs.jmedchem.5b00450.
Costales A, Mathur M, Ramurthy S, Lan J, Subramanian S, Jain R, et al. 2-Amino-7-substituted benzoxazole analogs as potent RSK2 inhibitors. Bioorg Med Chem Lett. 2014;24:1592–6. doi:10.1016/j.bmcl.2014.01.058.
Naud S, Westwood IM, Faisal A, Sheldrake P, Bavetsias V, Atrash B, et al. Structure-based design of orally bioavailable 1 H -pyrrolo[3,2- c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1). J Med Chem. 2013;56:10045–65. doi:10.1021/jm401395s.
Acknowledgements
P.P.G and V.A.B were granted the travel doctoral student exchange tuition in the framework of the Erasmus Mundus EUPHRATES project (3rd Cohort), 2016–2017.
Funding
This research was funded by Scientific Council of Lithuania (Scientific team project #MIP-033/2014); therefore, we thank the organization.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflicts of interest
The authors declare no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Gupta, P.P., Bastikar, V.A., Kuciauskas, D. et al. Molecular modeling and structure-based drug discovery approach reveals protein kinases as off-targets for novel anticancer drug RH1. Med Oncol 34, 176 (2017). https://doi.org/10.1007/s12032-017-1011-5
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s12032-017-1011-5