Virtual Screening for Type II B Inhibitors of B-RafV600E Kinase

Author(s): Kai-Xiong Qiu, Wen Zhang, Fang Yu, Wei Li, Zhong-Wen Sun, Shu-Qun Zhang, Ya-Juan Chen, Hui-Ding Xie*

Journal Name: Current Computer-Aided Drug Design

Volume 16 , Issue 3 , 2020

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Abstract:

Background: B-RafV600E kinase was identified as an important target in current cancer treatment, and the type II B inhibitors show good qualities in preclinical studies. Therefore, it is very important to discover novel II B inhibitors of B-RafV600E kinase.

Methods: In order to discover novel II B inhibitors of B-RafV600E kinase, virtual screening against ZINC database was performed by using a combination of pharmacophore modelling, molecular docking, 3DQSAR model and binding free energy (ΔGbind) calculation studies. The inhibitory activities against A375 cell lines of the hit compounds were tested by using MTT assay.

Results: Five promising hit compounds were obtained after screening, and all the five hit compounds showed good inhibitory rates against A375 cell lines.

Conclusion: The combined approach of the virtual screening in our work is effective, which can be used to discover novel inhibitors with a new skeleton. In addition, the five compounds obtained from the screening showed good inhibitory rates against A375 cell lines, which can be considered to develop new II B inhibitors of B-RafV600E kinase.

Keywords: B-RafV600E kinase, type II B inhibitors, virtual screening, pharmacophore modelling, molecular docking, 3DQSAR, binding free energy calculation.

[1]
Wellbrock, C.; Karasarides, M.; Marais, R. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol., 2004, 5(11), 875-885.
[http://dx.doi.org/10.1038/nrm1498] [PMID: 15520807]
[2]
Li, N.; Batt, D.; Warmuth, M. B-Raf kinase inhibitors for cancer treatment. Curr. Opin. Investig. Drugs, 2007, 8(6), 452-456.
[PMID: 17621874]
[3]
Mercer, K.E.; Pritchard, C.A. Raf proteins and cancer: B-Raf is identified as a mutational target. Biochim. Biophys. Acta, 2003, 1653(1), 25-40.
[PMID: 12781369]
[4]
Wan, P.T.; Garnett, M.J.; Roe, S.M.; Lee, S.; Niculescu-Duvaz, D.; Good, V.M.; Jones, C.M.; Marshall, C.J.; Springer, C.J.; Barford, D.; Marais, R. Cancer Genome Project. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 2004, 116(6), 855-867.
[http://dx.doi.org/10.1016/S0092-8674(04)00215-6] [PMID: 15035987]
[5]
Sawyers, C. Targeted cancer therapy. Nature, 2004, 432(7015), 294-297.
[http://dx.doi.org/10.1038/nature03095] [PMID: 15549090]
[6]
Wang, P.F.; Qiu, H.Y.; Wang, Z.F.; Zhang, Y.J.; Wang, Z.C.; Li, D.D.; Zhu, H.L. Identification of novel B-RafV600E inhibitors employing FBDD strategy. Biochem. Pharmacol., 2017, 132, 63-76.
[http://dx.doi.org/10.1016/j.bcp.2017.02.022] [PMID: 28267440]
[7]
Wang, P.F.; Zhang, Y.J.; Wang, D.; Hu, H.M.; Wang, Z.C.; Xu, C.; Qiu, H.Y.; Zhu, H.L. Design, synthesis, and biological evaluation of new B-RafV600E kinase inhibitors. Bioorg. Med. Chem., 2018, 26(9), 2372-2380.
[http://dx.doi.org/10.1016/j.bmc.2018.03.038] [PMID: 29602674]
[8]
Wang, X.; Kim, J. Conformation-specific effects of Raf kinase inhibitors. J. Med. Chem., 2012, 55(17), 7332-7341.
[http://dx.doi.org/10.1021/jm300613w] [PMID: 22808911]
[9]
El-Nassan, H.B. Recent progress in the identification of BRAF inhibitors as anti-cancer agents. Eur. J. Med. Chem., 2014, 72, 170-205.
[http://dx.doi.org/10.1016/j.ejmech.2013.11.018] [PMID: 24424304]
[10]
Ren, L.; Ahrendt, K.A.; Grina, J.; Laird, E.R.; Buckmelter, A.J.; Hansen, J.D.; Newhouse, B.; Moreno, D.; Wenglowsky, S.; Dinkel, V.; Gloor, S.L.; Hastings, G.; Rana, S.; Rasor, K.; Risom, T.; Sturgis, H.L.; Voegtli, W.C.; Mathieu, S. The discovery of potent and selective pyridopyrimidin-7-one based inhibitors of B-RafV600E kinase. Bioorg. Med. Chem. Lett., 2012, 22(10), 3387-3391.
[http://dx.doi.org/10.1016/j.bmcl.2012.04.015] [PMID: 22534450]
[11]
Wenglowsky, S.; Ren, L.; Grina, J.; Hansen, J.D.; Laird, E.R.; Moreno, D.; Dinkel, V.; Gloor, S.L.; Hastings, G.; Rana, S.; Rasor, K.; Sturgis, H.L.; Voegtli, W.C.; Vigers, G.; Willis, B.; Mathieu, S.; Rudolph, J. Highly potent and selective 3-N-methylquinazoline-4(3H)-one based inhibitors of B-Raf(V600E) kinase. Bioorg. Med. Chem. Lett., 2014, 24(8), 1923-1927.
[http://dx.doi.org/10.1016/j.bmcl.2014.03.007] [PMID: 24675381]
[12]
Wenglowsky, S.; Ren, L.; Ahrendt, K.A.; Laird, E.R.; Aliagas, I.; Alicke, B.; Buckmelter, A.J.; Choo, E.F.; Dinkel, V.; Feng, B.; Gloor, S.L.; Gould, S.E.; Gross, S.; Gunzner-Toste, J.; Hansen, J.D.; Hatzivassiliou, G.; Liu, B.; Malesky, K.; Mathieu, S.; Newhouse, B.; Raddatz, N.J.; Ran, Y.; Rana, S.; Randolph, N.; Risom, T.; Rudolph, J.; Savage, S.; Selby, L.T.; Shrag, M.; Song, K.; Sturgis, H.L.; Voegtli, W.C.; Wen, Z.; Willis, B.S.; Woessner, R.D.; Wu, W.I.; Young, W.B.; Grina, J. Pyrazolopyridine Inhibitors of B-Raf(V600E). Part 1: The Development of Selective, Orally Bioavailable, and Efficacious Inhibitors. ACS Med. Chem. Lett., 2011, 2(5), 342-347.
[http://dx.doi.org/10.1021/ml200025q] [PMID: 24900315]
[13]
Mathieu, S.; Gradl, S.N.; Ren, L.; Wen, Z.; Aliagas, I.; Gunzner-Toste, J.; Lee, W.; Pulk, R.; Zhao, G.; Alicke, B.; Boggs, J.W.; Buckmelter, A.J.; Choo, E.F.; Dinkel, V.; Gloor, S.L.; Gould, S.E.; Hansen, J.D.; Hastings, G.; Hatzivassiliou, G.; Laird, E.R.; Moreno, D.; Ran, Y.; Voegtli, W.C.; Wenglowsky, S.; Grina, J.; Rudolph, J. Potent and selective aminopyrimidine-based B-Raf inhibitors with favorable physicochemical and pharmacokinetic properties. J. Med. Chem., 2012, 55(6), 2869-2881.
[http://dx.doi.org/10.1021/jm300016v] [PMID: 22335519]
[14]
Richmond, N.J.; Abrams, C.A.; Wolohan, P.R.N.; Abrahamian, E.; Willett, P.; Clark, R.D. GALAHAD: 1. pharmacophore identification by hypermolecular alignment of ligands in 3D. J. Comput. Aided Mol. Des., 2006, 20(9), 567-587.
[http://dx.doi.org/10.1007/s10822-006-9082-y] [PMID: 17051338]
[15]
Shepphird, J.K.; Clark, R.D. A marriage made in torsional space: using GALAHAD models to drive pharmacophore multiplet searches. J. Comput. Aided Mol. Des., 2006, 20(12), 763-771.
[http://dx.doi.org/10.1007/s10822-006-9070-2] [PMID: 17016746]
[16]
Andrade, C.H.; Salum, L.B.; Pasqualoto, K.F.M.; Ferreira, E.I.; Andricopulo, A.D. Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents. Lett. Drug Des. Discov., 2008, 5, 377-387.
[http://dx.doi.org/10.2174/157018008785777289]
[17]
Cramer, R.D.; Patterson, D.E.; Bunce, J.D. Comparative molecular field analysis (CoMFA). 1. Effect of shape on binding of steroids to carrier proteins. J. Am. Chem. Soc., 1988, 110(18), 5959-5967.
[http://dx.doi.org/10.1021/ja00226a005] [PMID: 22148765]
[18]
Klebe, G.; Abraham, U.; Mietzner, T. Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity. J. Med. Chem., 1994, 37(24), 4130-4146.
[http://dx.doi.org/10.1021/jm00050a010] [PMID: 7990113]
[19]
Case, D.A.; Darden, T.A.; Cheatham, T.E.; Simmerling, C.L., III; Wang, J.; Duke, R.E.; Luo, R.; Walker, R.C.; Zhang, W.; Merz, K.M. AMBER 12, University of California, San Francisco, CA, USA , 2012.
[20]
Jakalian, A.; Bush, B.L.; Jack, D.B.; Bayly, C.I. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method. J. Comput. Chem., 2000, 21, 132-146.
[http://dx.doi.org/10.1002/(SICI)1096-987X(20000130)21:2<132:AID-JCC5>3.0.CO;2-P]
[21]
Jorgensen, W.L.; Chandrasekhar, J.; Madura, J.D.; Impey, R.W.; Klein, M.L. Comparison of simple potential functions for simulating liquid water. J. Chem. Phys., 1983, 79, 926-935.
[http://dx.doi.org/10.1063/1.445869]
[22]
Ryckaert, J.P.; Ciccotti, G.; Berendsen, H.J.C. Numerical integration of the Cartesian equations of motion of a system with constraints: Molecular dynamics of n-alkanes. J. Comput. Phys., 1977, 23, 327-341.
[http://dx.doi.org/10.1016/0021-9991(77)90098-5]
[23]
Miller, B.R., III; McGee, T.D., Jr; Swails, J.M.; Homeyer, N.; Gohlke, H.; Roitberg, A.E. MMPBSA.py: An efficient program for end-state free energy calculations. J. Chem. Theory Comput., 2012, 8(9), 3314-3321.
[http://dx.doi.org/10.1021/ct300418h] [PMID: 26605738]
[24]
Caballero, J. 3D-QSAR (CoMFA and CoMSIA) and pharmacophore (GALAHAD) studies on the differential inhibition of aldose reductase by flavonoid compounds. J. Mol. Graph. Model., 2010, 29(3), 363-371.
[http://dx.doi.org/10.1016/j.jmgm.2010.08.005] [PMID: 20863730]
[25]
Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model., 2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID: 15667143]
[26]
Xie, H.; Chen, L.; Zhang, J.; Xie, X.; Qiu, K.; Fu, J. A combined pharmacophore modeling, 3D QSAR and virtual screening studies on imidazopyridines as B-Raf inhibitors. Int. J. Mol. Sci., 2015, 16(6), 12307-12323.
[http://dx.doi.org/10.3390/ijms160612307] [PMID: 26035757]
[27]
Jain, A.N. Surflex: fully automatic flexible molecular docking using a molecular similarity-based search engine. J. Med. Chem., 2003, 46(4), 499-511.
[http://dx.doi.org/10.1021/jm020406h] [PMID: 12570372]
[28]
Hou, T.; Wang, J.; Li, Y.; Wang, W. Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J. Chem. Inf. Model., 2011, 51(1), 69-82.
[http://dx.doi.org/10.1021/ci100275a] [PMID: 21117705]
[29]
Tuveson, D.A.; Weber, B.L.; Herlyn, M. BRAF as a potential therapeutic target in melanoma and other malignancies. Cancer Cell, 2003, 4(2), 95-98.
[http://dx.doi.org/10.1016/S1535-6108(03)00189-2] [PMID: 12957284]


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VOLUME: 16
ISSUE: 3
Year: 2020
Published on: 03 June, 2020
Page: [222 - 230]
Pages: 9
DOI: 10.2174/1573409915666190130162821
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