抑制剂RVX08、SF2535、RVXOH与BRD4蛋白第一结构域结合模式的分子动力学研究
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摘要
该工作采用分子动力学模拟和主成分分析等方法研究了抑制剂SF2535、RVX08和RVXOH与BRD4蛋白第一结构域(BRD4-1)的结合对BRD4-1蛋白构象的影响.此外,为进一步研究三个抑制剂与BRD4-1蛋白的结合能力,采用分子力学泊松-玻尔兹曼表面积(MM-PBSA)方法计算了抑制剂与BRD4-1蛋白的结合自由能.结果表明SF2535与BRD4-1蛋白的结合能力最强.本研究不仅有助于更好的了解BRD4-1的功能和内在动力学,而且还可为以BRD4-1为靶标的有效抗癌药物的研发提供理论基础.
In this work, conformational changes of bromodomain-containing protein 4(1)(BRD4-1) induced by bindings of inhibitor SF2535、RVX08 and RVXOH were investigated using molecular dynamics(MD) simulations and principal component analysis. Moreover, to further study binding modes of three inhibitors to BRD4-1, binding free energies of inhibitors to BRD4-1 were also calculated using molecular mechanics Poisson-Boltzmann surface area(MM-PBSA) method. The results indicate that SF2535 has the strongest binding ability to BRD4-1 protein. This study is not only helpful for better understanding function and internal dynamics of BRD4-1,but also can provide a theoretical basis for rational designs of effective anticancer drugs targeting BRD4-1.
In this work, conformational changes of bromodomain-containing protein 4(1)(BRD4-1) induced by bindings of inhibitor SF2535、RVX08 and RVXOH were investigated using molecular dynamics(MD) simulations and principal component analysis. Moreover, to further study binding modes of three inhibitors to BRD4-1, binding free energies of inhibitors to BRD4-1 were also calculated using molecular mechanics Poisson-Boltzmann surface area(MM-PBSA) method. The results indicate that SF2535 has the strongest binding ability to BRD4-1 protein. This study is not only helpful for better understanding function and internal dynamics of BRD4-1,but also can provide a theoretical basis for rational designs of effective anticancer drugs targeting BRD4-1.
引文
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[33] McLure K G,Gesner E M,Tsujikawa L,et al.RVX-208, an inducer of apoa-i in humans, is a bet bromodomain antagonist[J].PLOS ONE,2013,8(12):83190.
[34] Aldeghi M,Heifetz A,Bodkin M J,et al.Predictions of ligand selectivity from absolute binding free energy calculations[J]. Journal of the American Chemical Society, 2017,139(2):946-957.
[2]Kouzarides T.Acetylation:A regulatory modification to rival phosphorylation.[J]. The EMBO Journal, 2000, 19(6): 1176-1179.
[3]Cheng Z, Gong Y, Ma Y,et al. Inhibition of BET bromodomain targets genetically diverse glioblastoma [J]. Clinical Cancer Research, 2013, 19(7): 1748-1759.
[4]Na′ama A S, Shrvxo Hami E. Histone deacetylase inhibitors as therapeutic agents for acute central nervous system injuries [J]. Molecular Medicine, 2011, 17(5-6): 448-456.
[5]Filippakopoulos P,Picaud S,Mangos M,et al. Histone recognition and large-scale structural analysis of the human bromodomain family [J]. Cell, 2012, 149(1): 214-231.
[6]Jang M K, Mochizuki K,Zhou M, et al. The bromodomain protein BRD4 is a positive regulatory component of P-TEFb and stimulates RNA Polymerase II-Dependent Transcription [J]. Molecular Cell, 2005, 19(4): 523-534.
[7]Dey A, Nishiyama A, Karpova T, et al. BRD4 marks select genes on mitotic chromatin and directs postmitotic transcription [J]. Molecular Biology of the Cell, 2009, 20(23): 4899-4909.
[8]Hussong M, B?rno S T,Kerick M,et al.The bromodomain protein BRD4 regulates the KEAP1/NRF2-dependent oxidative stress response [J]. Cell Death Disease, 2014, 5(4):1195.
[9]Haynes S R,Dollard C,Winston F,et al.The bromodomain:A conserved sequence found in human,drosophila and yeast proteins [J]. Nucleic acids Research, 1992, 20(10): 2603.
[10] Dawson M A, Kouzarides T,Huntly B J.Targeting epigenetic readers in cancer [J]. New England Journal of Medicine, 2012, 367(18): 647-657.
[11] Winston F,Allis C D. The bromodomain:A chromatin-targeting module.[J]. Nature Structural Biology,1999,6(7):601-604.
[12] Gao X,Wu X,Zhang X,et al. Inhibition of BRD4 suppresses tumor growth and enhances iodine uptake in thyroid cancer [J]. Biochemical and Biophysical Research Communications, 2016, 469(3): 679-685.
[13] Lucas X,WRVXOHlwend D,Hügle M,et al. 4-Acyl pyrroles:Mimicking acetylated lysines in histone code reading [J]. Angewandte Chemie, 2013, 52(52): 14055-14059.
[14] Raj U,Kumar H,Varadwaj P K. Molecular docking and dynamics simulation study of flavonoids as BET bromodomain inhibitors [J]. Journal of Biomolecular Structure Dynamics, 2016, 35(11): 1-12.
[15] Kuang M,Zhou J,Wang L,et al. Binding kinetics versus affinities in BRD4 inhibition [J]. Journal of Chemical Information Modeling, 2015, 55(9): 1926-1935.
[16] Allen B K,Mehta S,Ember S W J,et al.Large-scale computational screening identifies first in class multitarget inhibitor of EGFR kinase and BRD4 [J]. Scientific Reports, 2015, 5(16924): 1-16.
[17] Chen J,Wang X,Zhu,T,et al.A comparative insight into amprenavir resistance of mutations V32I, G48V, I50V, I54V, and I84V in HIV-1 protease based on thermodynamic integration and MM-PBSA methods[J].Journal of Chemical Information and Modeling,2015,55(9),1903-1913.
[18] Chen J,Wang J,Zhu W.L1196M-induced conformational changes and the drug resistant mechanism of anaplastic lymphoma kinase studied by free energy perturbation and umbrella sampling[J]. Physical Chemistry Chemical Physics,2017, 19(44), 30239-30248.
[19] Chen J, Wang J,Zhu W.Zinc ion-induced conformational changes in new delphi metallo-β-lactamase 1 probed by molecular dynamics simulations and umbrella sampling[J]. Physical Chemistry Chemical Physics, 2017,19:3067-3075.
[20] Bas D C,Rogers D M,Jensen J H. Very fast prediction and rationalization of pka values for protein-ligand complexes[J]. Proteins: Structure, Function, and Bioinformatics, 2008,73(3),765-783.
[21] Li H,Robertson A D,Jensen J H.Very fast empirical prediction and rationalization of protein pka values [J]. Proteins:Structure Function Bioinformatics, 2005, 61(4): 704-721.
[22] Jakalian A,Jack D B,Bayly C I. Fast, efficient generation of high-quality atomic charges. AM1-BCC model: I. Method [J]. Journal of Computational Chemistry, 2002,23(16):132-146.
[23] Lindorfflarsen K,Piana S,Palmo K,et al. Improved side-chain torsion potentials for the Amber FF99SB protein force field [J]. Proteins:Structure Function Bioinformatics, 2010, 78(8):1950-1958.
[24] Wang J,Wolf R M,Caldwell J W, et al. Development and testing of a general Amber force field [J]. Journal of Computational Chemistry, 2004, 25(9): 1157-1174.
[25] Jorgensen W L, Chandrasekhar J,Madura J D,et al. Comparison of simple potential functions for simulating liquid water [J]. Journal of Chemical Physics, 1983, 79(2): 926-935.
[26] Coleman T G, Mesick H C,Darby R L. Numerical integration [J]. Annals of Biomedical Engineering, 1977, 5(4): 322-328.
[27] Izaguirre J A, Catarello D P,Wozniak J M,et al. Langevin stabilization of molecular dynamics [J]. Journal of Chemical Physics, 2001, 114(5): 2090-2098.
[28] Essmann U,Perera L,Berkowitz M L,et al. A smooth particle mesh Ewald method [J]. Journal of Chemical Physics, 1995, 103(19): 8577-8593.
[29] Levy R M,Srinivasan A R,Olson W K,et al. Quasi-harmonic method for studying very low frequency modes in proteins [J]. Biopolymers, 1984, 23(6): 1099-1112.
[30] Case D A,Cheatham T E,Darden T,et al.The Amber biomolecular simulation programs [J]. Journal of Computational Chemistry, 2005, 26(16): 1668-1688.
[31] Laberge M,Yonetani T.Molecular dynamics simulations of hemoglobin a in different states and bound to DPG: Effector-linked perturbation of tertiary conformations and HBA concerted dynamics [J]. Biophysical Journal, 2008 , 94(7): 2737-2751.
[32] Andrews F H,Singh A R,Joshi S,et al. Kutateladze, T. G. Dual-activity PI3K-BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis[J]. Proceedings of the National Academy of Sciences, 2017,114(7):1072-1080.
[33] McLure K G,Gesner E M,Tsujikawa L,et al.RVX-208, an inducer of apoa-i in humans, is a bet bromodomain antagonist[J].PLOS ONE,2013,8(12):83190.
[34] Aldeghi M,Heifetz A,Bodkin M J,et al.Predictions of ligand selectivity from absolute binding free energy calculations[J]. Journal of the American Chemical Society, 2017,139(2):946-957.