Abstract
Background: B-Raf has become an important and exciting therapeutic cancer target.
Methods: In the present work, molecular modeling protocols like molecular docking, MM/GBSA calculations, 3D-QSAR and binding site detection were performed on a dataset of 41 Type II inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase. Furthermore, the good linear relationships between G-Scores and MM/GBSA calculated and the experimental activity were shown. The satisfactory CoMFA and CoMSIA were constructed based on the conformations obtained by molecular docking.
Results: The key structural requirements for increasing biological activity were verified by analyzing 3D contour maps of the 3D-QSAR models. FTMap and SiteMap were also used to detect the more efficient active binding site.
Conclusion: New inhibitors were synthesized and the biological activities were evaluated, the results further validated our design strategy.
Keywords: B-Raf kinase Type-II inhibitors, molecular docking, MM/PBSA, CoMFA, CoMSIA, binding site detection.
Graphical Abstract
[1]
Santarpia, L.; Lippman, S.M.; El-Naggar, A.K. Targeting the MAPK–RAF signalling pathway in cancer therapy. Expert Opin. Ther. Targets, 2012, 16, 103-109.
[2]
Ribas, A.; Flaherty, K.T. BRAF targeted therapy changes the treatment paradigm in melanoma. Nat. Rev. Clin. Oncol., 2011, 8, 426-433.
[3]
Rebocho, A.P. Marais R. ARAF acts as a scaffold to stabilize BRAF, CRAF heterodimers. Oncogene, 2013, 32(26), 3207-3212.
[4]
Mooz, J.; Oberoi-Khanuja, T.K.; Harms, G.S. Dimerization of the kinase. ARAF promotes MAPK pathway activation and cell migration. Sci. Signal., 2014, 7(337), ra73.
[5]
Rebocho, A.P. Marais, R. New insight puts CRAF in sight as a therapeutic target. Cancer Discov., 2011, 1(2), 98-109.
[6]
Maurer, G.; Tarkowski, B.; Baccarini, M. Raf kinases in cancer-roles and therapeutic opportunities. Oncogene, 2011, 30(32), 3477-3488.
[7]
Fransén, K.; Klintenäs, M.; Österström, A. Mutation analysis of the BRAF, ARAF and RAF-1 genes in human colorectal adenocarcinomas. Carcinogenesis, 2004, 25(4), 527-533.
[8]
Tiacci, E.; Trifonov, V.; Schiavoni, G. BRAF mutations in hairy-cell leukemia. New. Engl. J. Med., 2011, 364(24), 2305-2315.
[10]
Wan, P.T.C.; Garnett, M.J.; Roe, S.M. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell, 2004, 116(6), 855-867.
[11]
Wang, X.; Kim, J. Conformation-Specific Effects of Raf Kinase Inhibitors, Miniperspective. J. Med. Chem., 2012, 55(17), 7332-7341.
[12]
Backes, A.C.; Zech, B.; Felber, B. Small-molecule inhibitors binding to protein kinase. Part II, the novel pharmacophore approach of type II and type III inhibition. Expert Opin. Drug Discov., 2008, 3(12), 1427-1449.
[13]
McArthur, G.A.; Chapman, P.B.; Robert, C. Safety and efficacy of vemurafenib in BRAF V600E and BRAF V600K mutation-positive melanoma (BRIM-3), extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol., 2014, 15(3), 323-332.
[14]
Flaherty, K.T.; Puzanov, I.; Kim, K.B. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med., 2010, 363(9), 809-819.
[15]
Sosman, J.A.; Kim, K.B.; Schuchter, L. Survival in BRAF V600–mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med., 2012, 366(8), 707-714.
[16]
Sanchez-Laorden, B.; Viros, A.; Girotti, M.R. BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci. Signal., 2014, 7(318), ra30.
[17]
Arora, R.; Di, M.M.; Stes, E. Structural investigation of B-Raf paradox breaker and inducer inhibitors. J. Med. Chem., 2015, 58(4), 1818-1831.
[18]
Wolin, R.L.; Bembenek, S.D.; Wei, J. Dual binding site inhibitors of B-RAF kinase. Bioorg. Med. Chem. Lett., 2008, 18(9), 2825-2829.
[19]
Smith, A.L.; DeMorin, F.F.; Paras, N.A. Selective inhibitors of the mutant B-Raf pathway, discovery of a potent and orally bioavailable aminoisoquinoline. J. Med. Chem., 2009, 52(20), 6189-6192.
[20]
Yang, W.; Chen, Y.; Zhou, X. Design, synthesis and biological evaluation of bisaryl ureas and amides based on 2-amino-3-purinylpyridine scaffold as DFG-out B-Raf kinase inhibitors. Eur. J. Med. Chem., 2015, 89, 581-596.
[21]
Guariento, S.; Franchini, S.; Tonelli, M. Exhaustive CoMFA and CoMSIA analyses around different chemical entities, a ligand-based study exploring the affinity and selectivity profiles of 5-HT1A ligands. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 214-230.
[22]
Vrontaki, E.; Melagraki, G.; Mavromoustakos, T. Searching for anthranilic acid-based thumb pocket 2 HCV NS5B polymerase inhibitors through a combination of molecular docking, 3D-QSAR and virtual screening. J. Enzyme Inhib. Med. Chem., 2016, 31(1), 38-52.
[23]
Liu, H.C.; Lu, S.; Ran, T. Accurate Activity Predictions of B-Raf Type II Inhibitors via Molecular Docking and QSAR Methods. Acta Phys. Chim. Sin., 2015, 31(11), 2191-2206.
[24]
Ghasemi, J.B.; Meftahi, N. Docking, CoMFA and CoMSIA studies of a series of sulfonamides derivatives as carbonic anhydrase I inhibitors. J. Enzyme Inhib. Med. Chem., 2013, 28, 320-327.
[25]
Hao, M.; Li, Y.; Zhang, S.W. Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies. J. Enzyme Inhib. Med. Chem., 2011, 26(6), 792-804.
[26]
Lan, P.; Sun, J.R.; Chen, W.N. Molecular modelling studies on d-annulated benzazepinones as VEGF-R2 kinase inhibitors using docking and 3D-QSAR. J. Enzyme Inhib. Med. Chem., 2011, 26(3), 367-377.
[27]
Lu, X.; Chen, Y.; You, Q. 3D-QSAR, molecular docking studies, and binding mode prediction of thiolactomycin analogs as mtFabH inhibitors. J. Enzyme Inhib. Med. Chem., 2010, 25(2), 240-249.
[28]
Zhuang, S.L.; Wang, H.F.; Ding, K.K.; Wang, J.Y.; Pan, L.M.; Lu, Y.L.; Liu, Q.J.; Zhang, C.L. Interactions of benzotriazole UV stabilizers with human serum albumin, atomic insights revealed by biosensors, spectroscopies and molecular dynamics simulations. Chemosphere, 2016, 144, 1050-1059.
[30]
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.
[31]
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), 4130-4160.
[32]
Ngan, C.H.; Bohnuud, T.; Mottarella, S.E. FTMAP, extended protein mapping with user-selected probe molecules. Nucleic Acids Res., 2012, 40, W271-5.
[34]
Cross, J.B.; Thompson, D.C.; Rai, B.K.; Baber, J.C.; Fan, K.Y.; Hu, Y.; Humblet, C. Comparison of several molecular docking programs, pose prediction and virtual screening accuracy. J. Chem. Inf. Model., 2009, 49(6), 1455-1474.
[35]
Srivastava, H.K.; Sastry, G.N. Molecular dynamics investigation on a series of HIV protease inhibitors, assessing the performance of MM-PBSA and MM-GBSA approaches. J. Chem. Inf. Model., 2012, 52(11), 3088-3098.
[36]
Munnaluri, R.; Sivan, S.K.; Manga, V. Molecular docking and MM/GBSA integrated protocol for designing small molecule inhibitors against HIV-1 gp41. Med. Chem. Res., 2015, 24(2), 829-841.
[37]
Geladi, P. Notes on the history and nature of Partial Least Squares (PLS) modelling. J. Chemom., 1998, 2(4), 231-246.
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