Skip to main content
SpringerLink
Log in

Computational investigation on inhibition mechanism of BRAFV600E by Vemurafenib (PLX4032) and its analogue PLX4720

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

BRAFV600E small-molecule inhibitors have recently received increasing attention as very effective agents for the therapy of cancer, especially melanoma. In this current work, a computational investigation was performed to investigate the interaction details of BRAFV600E kinase with inhibitors Vemurafenib (PLX4032) and its analog PLX4720. Binding free energy calculations based on molecular dynamics simulations reveal that ligands PLX4032 and PLX4720 bind to and stabilize the DFG-in conformation of BRAFV600E. Component analysis of binding free energy revealed that vdWaals interactions play a dominating effect on BRAFV600E inhibition. Furthermore, the per-residue binding free energy decomposition revealed that the most favorable contribution came from Ile463, Val471, Ala481, Lys483, Leu514, Ile527, Thr529, Gln530, Trp531, Cys532, Phe583, Gly593, and Asp594. These results agree well with experimental data, which provide valuable resources for understanding the inhibition mechanism of BRAFV600E by PLX4032 and PLX4720 and clues for the design of novel potent BRAFV600E inhibitors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a web-based environment for protein structure homology modelling. Bioinformatics 22:195–201

    Article  CAS  PubMed  Google Scholar 

  • Bayly CI, Cieplak P, Cornell W, PKollman PA (1993) A well behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model. J Phys Chem 97:10269–10280

    Article  CAS  Google Scholar 

  • Benkert P, Biasini M, Schwede T (2011) Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27:343–350

    Article  CAS  PubMed  Google Scholar 

  • Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton Elizabeth A, Bernice Wong, Garson Tsang, Powell B, West Brian L, Shellooe R, Marimuthu A, Nguyen H, Zhang KYJ, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D’Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K (2010) Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596–599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bollag G, Tsai J, Zhang J, Zhang C, Ibrahim P, Nolop K, Hirth P (2012) Vemurafenib: the first drug approved for BRAF-mutant cancer. Nat Rev Drug Discov 11(11):873–86

    Article  CAS  PubMed  Google Scholar 

  • Case DA, Darden TA, Cheatham III TE, Simmerling CL, Wang J, Duke RE, Luo R, Walker RC, Zhang W, Merz KM, Roberts B, Hayik S, Roitberg A, Seabra G, Swails J, Goetz AW, Kolossváry I, Wong KF, Paesani F, Vanicek J, Wolf RM, Liu J, Wu X, Brozell SR, Steinbrecher T, Gohlke H, Cai Q, Ye X, Wang J, Hsieh MJ, Cui G, Roe DR, Mathews DH, Seetin MG, Salomon-Ferrer R, Sagui C, Babin V, Luchko T, Gusarov S, Kovalenko A, Kollman PA (2012) AMBER 12. University of California, San Francisco

    Google Scholar 

  • 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 

  • Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA (2002) Mutations of the BRAF gene in human cancer. Nature 417:949–954

    Article  CAS  PubMed  Google Scholar 

  • El-Nassan HB (2014) Recent progress in the identification of BRAF inhibitors as anticancer Agents. Eur J Med Chem 72:170–205

    Article  CAS  PubMed  Google Scholar 

  • Emuss V, Garnett M, Mason C, Marais R (2005) Mutations of C-RAF are rare in human cancer because C-RAF has a low basal kinase activity compared with B-RAF. Cancer Res 65:9719–9726

    Article  CAS  PubMed  Google Scholar 

  • Frisch M, Trucks G, Schlegel H, Scuseria G, Robb M, Cheeseman J, Montgomery Jr J, Vreven T, Kudin K, Burant J (2004) Gaussian 03. Gaussian, Inc., Wallingford, CT

    Google Scholar 

  • Garnett MJ, Marais R (2004) Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6:313–319

    Article  CAS  PubMed  Google Scholar 

  • Gray-Schopfer V, Wellbrock C, Marais R (2007) Melanoma biology and new targeted therapy. Nature 445:851–857

    Article  CAS  PubMed  Google Scholar 

  • Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C (2006) Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins 65:712–725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935

    Article  CAS  Google Scholar 

  • Karasarides M, Chiloeches A, Hayward R, Niculescu-Duvaz D, Scanlon I, Friedlos F, Ogilvie L, Hedley D, Martin J, Marshall CJ, Springer CJ, Marais R (2004) B-RAF is a therapeutic target in melanoma. Oncogene 23:6292–6298

    Article  CAS  PubMed  Google Scholar 

  • Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–897

    Article  CAS  PubMed  Google Scholar 

  • Leicht DT, Balan V, Kaplun A, Singh-Gupta V, Kaplun L, Dobson M, Tzivion G (2007) Raf kinases: function, regulation and role in human cancer. Biochim Biophys Acta 1773(8):1196–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Niault TS, Baccarini M (2010) Targets of Raf in tumorigenesis. Carcinogenesis 31:1165–1174

    Article  CAS  PubMed  Google Scholar 

  • Roberts PJ, Der CJ (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene 26:3291–3310

    Article  CAS  PubMed  Google Scholar 

  • Ryckaert JP, Ciccotti G, Berendsen HJC (1977) Numerical integration of the Cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23:327–341

    Article  CAS  Google Scholar 

  • Salomon-Ferrer R, Götz AW, Poole D, Le Grand S, Walker RC (2013) Routine microsecond molecular dynamics simulations with AMBER on GPUs. 2. Explicit solvent particle mesh Ewald. J Chem Theory Comput 9:3878–3888

    Article  CAS  PubMed  Google Scholar 

  • Tsai J, Lee JT, Wang W, Zhang J, Cho H, Mamo S, Bremer R, Gillette S, Kong J, Haass NK, Sproesser K, Li L, Smalley KS, Fong D, Zhu YL, Marimuthu A, Nguyen H, Lam B, Liu J, Cheung I, Rice J, Suzuki Y, Luu C, Settachatgul C, Shellooe R, Cantwell J, Kim SH, Schlessinger J, Zhang KY, West BL, Powell B, Habets G, Zhang C, Ibrahim PN, Hirth P, Artis DR, Herlyn M, Bollag G (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci USA 105(8):3041–3046

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tuveson DA, Weber BL, Herlyn M (2003) BRAF as a potential therapeutic target in melanoma and other malignancies. Cancer Cell 4:95–98

    Article  CAS  PubMed  Google Scholar 

  • Wan PT, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, Jones CM, Marshall CJ, Springer CJ, Barford D, Marais R (2004) Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 116:855–867

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25:1157–1174

    Article  CAS  PubMed  Google Scholar 

  • Wellbrock C, Karasarides M, Marais R (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5:875–885

    Article  CAS  PubMed  Google Scholar 

  • Wu X, Wan S, Wang G, Jin H, Li Z, Tian Y, Zhu Z, Zhang J (2015) Molecular dynamics simulation and free energy calculation studies of kinase inhibitors binding to active and inactive conformations of VEGFR-2. J Mol Graph Model 56:103–112

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No.81202413 and No. 81573263) and National Natural Science Foundation of Guangdong, China (No. 2015A030313285). The calculations of the ligands were performed in the China ScGrid of Supercomputing Center of Chinese Academy of Science.

Author information

Authors and Affiliations

  1. Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, People’s Republic of China

    XiaoYun Wu, Yu Fu, YuanYuan Wang, ShanHe Wan & JiaJie Zhang

Authors
  1. XiaoYun Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. YuanYuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. ShanHe Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. JiaJie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to XiaoYun Wu or JiaJie Zhang.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wu, X., Fu, Y., Wang, Y. et al. Computational investigation on inhibition mechanism of BRAFV600E by Vemurafenib (PLX4032) and its analogue PLX4720. Med Chem Res 26, 390–396 (2017). https://doi.org/10.1007/s00044-016-1757-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-016-1757-x

Keywords

Search

Navigation