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De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach

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Abstract

Vascular endothelial growth factor receptor-2 (VEGFR-2) tyrosine kinase inhibitors have been demonstrated to possess substantial antitumor activity. VEGFR-2 tyrosine kinase inhibitors are crucial for development of antitumor drugs. Based on the crystal structure of VEGFR-2 tyrosine kinase, a linked-fragment strategy was employed to design novel VEGFR-2 tyrosine kinase inhibitors, and 1000 compounds were generated in this process. Absorption, distribution, metabolism, excretion and toxicity (ADMET) were used to screen the 1000 compounds, and 59 compounds were acceptable. Scaffold hopping was then used for further screening, and only four compounds were obtained in this way. Then, the binding energy of the four molecules to VEGFR-2 tyrosine kinase was calculated using molecular docking, and their values were found to be lower than that of Sorafenib. Finally, molecular dynamics simulations were performed on the complex of the compound with the lowest binding energy with VEGFR-2 tyrosine kinase, and the binding model was analyzed. At the end, four chemical entities with novel structures were obtained, and were suggested for experimental testing in future studies.

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References

  1. Shah MA, Wainberg ZA, Catenacci DV, Hochster HS, Ford J, Kunz P, Lee F-C, Kallender H, Cecchi F, Rabe DC (2013) Phase II study evaluating 2 dosing schedules of oral foretinib (GSK1363089), cMET/VEGFR2 inhibitor, in patients with metastatic gastric cancer. PLoS One 8:e54014

    Article  CAS  Google Scholar 

  2. McDonnell C, Hill A, McNamara D, Walsh T, Bouchier-Hayes D (2000) REVIEWS—Tumour micrometastases: the influence of angiogenesis. Eur J Surg Oncol 26:105–115

    Article  CAS  Google Scholar 

  3. Steri V, Ellison TS, Gontarczyk AM, Weilbaecher K, Schneider JG, Edwards D, Fruttiger M, Hodivala-Dilke KM, Robinson SD (2014) Acute depletion of endothelial β3-integrin transiently inhibits tumor growth and angiogenesis in mice. Circ Res 114:79–91

    Article  CAS  Google Scholar 

  4. Deng YH, Xu D, Su YX, Cheng YJ, Yang YL, Wang XY, Zhang J, You QD, Sun LP (2015) Synthesis and biological evaluation of novel oxazolo [5, 4‐d] pyrimidines as potent VEGFR‐2 inhibitors. Chem Biodivers 12:528–537

    Article  CAS  Google Scholar 

  5. Takahashi Y, Kitadai Y, Bucana CD, Cleary KR, Ellis LM (1995) Expression of vascular endothelial growth factor and its receptor, KDR, correlates with vascularity, metastasis, and proliferation of human colon cancer. Cancer Res 55:3964–3968

    CAS  Google Scholar 

  6. Poon RT-P, Lau C, Yu W-C, Fan S-T, Wong J (2004) High serum levels of vascular endothelial growth factor predict poor response to transarterial chemoembolization in hepatocellular carcinoma: a prospective study. Oncol Rep 11:1077–1084

    CAS  Google Scholar 

  7. Schenone S, Bondavalli F, Botta M (2007) Antiangiogenic agents: an update on small molecule VEGFR inhibitors. Curr Med Chem 14:2495–2516

    Article  CAS  Google Scholar 

  8. Zhong H, Phillip Bowen J (2011) Recent advances in small molecule inhibitors of VEGFR and EGFR signaling pathways. Curr Top Med Chem 11:1571–1590

    Article  CAS  Google Scholar 

  9. Musumeci F, Radi M, Brullo C, Schenone S (2012) Vascular endothelial growth factor (VEGF) receptors: drugs and new inhibitors. J Med Chem 55:10797–10822

    Article  CAS  Google Scholar 

  10. Kang C-M, Liu D-Q, Zhao X-H, Dai Y-J, Cheng J-G, Lv Y-T (2015) QSAR and molecular docking studies on oxindole derivatives as VEGFR-2 tyrosine kinase inhibitors. J Recept Signal Transduct Res: 1–7

  11. Roskoski R (2008) VEGF receptor protein–tyrosine kinases: structure and regulation. Biochem Biophys Res Commun 375:287–291

    Article  CAS  Google Scholar 

  12. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE (2006) Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 24:16–24

    Article  CAS  Google Scholar 

  13. Harris PA, Boloor A, Cheung M, Kumar R, Crosby RM, Davis-Ward RG, Epperly AH, Hinkle KW, Hunter RN III, Johnson JH (2008) Discovery of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-benzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor. J Med Chem 51:4632–4640

    Article  CAS  Google Scholar 

  14. Ho TH, Jonasch E (2011) Axitinib in the treatment of metastatic renal cell carcinoma. Future Oncol 7:1247–1253

    Article  CAS  Google Scholar 

  15. Commander H, Whiteside G, Perry C (2011) Vandetanib. Drugs 71:1355–1365

    Article  CAS  Google Scholar 

  16. Strumberg D, Scheulen M, Schultheis B, Richly H, Frost A, Büchert M, Christensen O, Jeffers M, Heinig R, Boix O (2012) Regorafenib (BAY 73–4506) in advanced colorectal cancer: a phase I study. Br J Cancer 106:1722–1727

    Article  CAS  Google Scholar 

  17. Kwak EL, Bang Y-J, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou S-HI, Dezube BJ, Jänne PA, Costa DB (2010) Anaplastic lymphoma kinase inhibition in non–small-cell lung cancer. New Eng J Med 363:1693–1703

    Article  CAS  Google Scholar 

  18. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (2004) UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem 25:1605–1612

    Article  CAS  Google Scholar 

  19. Eswar N, Webb B, Marti-Renom MA, Madhusudhan MS, Eramian D, Shen MY, Pieper U, Sali A (2007) Comparative protein structure modeling using MODELLER. Curr Protoc Protein Sci, Chapter 2, Unit 2

  20. Wang R, Liu L, Lai L, Tang Y (1998) SCORE: a new empirical method for estimating the binding affinity of a protein-ligand complex. Mol Model Ann 4:379–394

    Article  CAS  Google Scholar 

  21. Lagorce D, Sperandio O, Galons H, Miteva MA, Villoutreix BO (2008) FAF-Drugs2: free ADME/tox filtering tool to assist drug discovery and chemical biology projects. BMC Bioinformatics 9:396

    Article  Google Scholar 

  22. Reutlinger M, Koch CP, Reker D, Todoroff N, Schneider P, Rodrigues T, Schneider G (2013) Chemically advanced template search (CATS) for scaffold‐hopping and prospective target prediction for ‘orphan’ molecules. Mol Inform 32:133–138

    Article  CAS  Google Scholar 

  23. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31:455–461

    CAS  Google Scholar 

  24. Hess B, Kutzner C, Van Der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comput 4:435–447

    Article  CAS  Google Scholar 

  25. SchuÈttelkopf AW, Van Aalten DM (2004) PRODRG: a tool for high-throughput crystallography of protein–ligand complexes. Acta Crystallogr D 60:1355–1363

    Article  Google Scholar 

  26. van Gunsteren WF, Billeter S, Eising A, Hünenberger PH, Krüger P, Mark AE, Scott W, Tironi IG (1996) Biomolecular simulation: the GROMOS96 manual and user guide. ETH Zurich, Switzerland

  27. Berendsen HJC, Postma JPM, Gunsteren WFV, Hermans J (1981) Interaction models for water in relation to protein hydration. Springer, Dordrecht

    Book  Google Scholar 

  28. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: an N⋅log(N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092

    Article  CAS  Google Scholar 

  29. Hess B, Bekker H, Berendsen HJC, Fraaije JGEM (2008) LINCS: a linear constraint solver for molecular simulations. J Chem Theory Comput 4:1463–1472

    Google Scholar 

  30. Bussi G, Donadio D, Parrinello M (2007) Canonical sampling through velocity rescaling. J Chem Phys 126:014101–014101

    Article  Google Scholar 

  31. Parrinello M, Rahman A (1981) Polymorphic transitions in single crystals: a new molecular dynamics method. J Appl Phys 52:7182–7190

    Article  CAS  Google Scholar 

  32. Yuan Y, Pei J, Lai L (2011) LigBuilder 2: a practical de novo drug design approach. J Chem Inf Model 51:1083–1091

    Article  CAS  Google Scholar 

  33. Kumari R, Kumar R, Lynn A (2014) g_mmpbsa A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54:1951–1962

    Article  CAS  Google Scholar 

  34. Baker NA, Sept D, Joseph S, Holst MJ, McCammon JA (2001) Electrostatics of nanosystems: application to microtubules and the ribosome. Proc Natl Acad Sci USA 98:10037–10041

    Article  CAS  Google Scholar 

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Acknowledgments

The project was supported by the National Natural Science Foundation of China (21272131, 81502977), and Fundamental Research Funds for the Central Universities(3008000–841512007).

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Authors and Affiliations

  1. College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao, 266042, People’s Republic of China

    Yi-zhou Liu, Xiao-li Wang, Xin-ying Wang, Dong-qing Liu & Cong-min Kang

  2. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People’s Republic of China

    Ri-lei Yu

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  1. Yi-zhou Liu
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  2. Xiao-li Wang
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  3. Xin-ying Wang
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Correspondence to Cong-min Kang.

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Liu, Yz., Wang, Xl., Wang, Xy. et al. De novo design of VEGFR-2 tyrosine kinase inhibitors based on a linked-fragment approach. J Mol Model 22, 222 (2016). https://doi.org/10.1007/s00894-016-3088-8

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  • DOI: https://doi.org/10.1007/s00894-016-3088-8

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