组蛋白去乙酰化酶及其抑制剂相互作用的分子模拟
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摘要
The modulation of the acetylation state of core histones plays a pivotal role in the regulation of gene expression.Acetylation and deacetylation of histones are controlled by two corresponding enzymes,histone acetyltransferases and histone deacetylases(HDACs). Inhibitors of histone deacetylases are well known as a new and promising class of anticancer agents.They induce growth arrest,cell differentiation and apoptosis in tumor cells.The HDACs belong to four structurally and functionally different phylogenetic classes.ClassⅠ(1, 2,3,8),classⅡ(4-7,9,10) and classⅣ(HDAC11) are zinc dependent proteases,and the classⅢHDACs are NAD~+ dependent enzymes.The active site of HDACs has been uncovered on the basis of the crystal structure HDLP and HDAC8.But it is far from being completely elucidated that why variant inhibitors have different inhibitory activities.The selectivity of HDACs inhibitors is also unknown.As far as the structure is concerned, cyclopeptide inhibitors have larger surface recognition cap groups,which would be important for their selectivity toward HDACs isoforms.
Apicidin and its three analogues(apicidin B,apicidin C and analogue d) are all cyclopeptide HDACs inhibitors.The experimental IC_(50) values of the four HDACs inhibitors toward HDAC1 are 1,10,6 and 86 nM,respectively,while the IC_(50) of apicidin toward HDAC8 is above 1000 nM.In this paper,the interactions between the HDACs and their inhibitors are studied by molecular simulation.A 3D structure model of human HDAC1 is constructed based on the crystal structure of human HDAC8,and the model quality is checked by several validation tests.Furthermore,the cyclopeptides apicidin and its analogues (apicidin B,apicidin C and analogue d) are docked to the HDAC1 model and HDAC8 to analyze the possibly binding modes.Finally,molecular dynamics studies are performed on the HDAC1-apicidin and HDAC8-apicidin complexes to search their structural stability.
At the entrance portion of the active pocket,there are Glu98 and Arg270 in HDAC1 instead of Tyr100 and Met274 comparing with HDAC8.This change makes the pocket entrance more open in HDAC1,indicating that those inhibitors with large cap groups might bind to the active site in a more favorable manner.The keto-carbonyl moiety of cyclopeptides chelating with zinc ion is the basis of low binding energy,which means high inhibitory activity.The analogue d contacts less residues of HDAC1 than apicidin does,which is consistent with its lower inhibitory activity(△G_(binding)=-8.54 kcal/mol) comparing with apicidin(△G_(binding)= -9.67 kcal/mol).The docking results of apicidin and HDAC8 indicate that,the cyclopeptides are apt to bind to the second cavity near the active pocket instead of coordinating with Zn~(2+). When apicidin binding to the second cavity of HDAC8,it forms less stable interactions with the enzyme and can not inhibit the acetylated sidechains of lysine of histone entering the active pocket.This could be an explanation for the selectivity of apicidin toward HDAC1 and HDAC8.The molecular dynamics simulation results shows that,the Arg270 locating at the entrance of the HDAC1 active pocket plays a crucial role in forming stable interactions with apicidin.There are two lasting hydrogen bonds between apicidin and HDAC1 during the molecular dynamics simulation,while none between apicidin and HDAC8.This difference could be another important reason for the high inhibitory activity of apicidin to HDAC1.This study would be helpful for the optimization of cyclopeptide HDAC inhibitors,especially for the design of selective HDACs inhibitors.
引文
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[26]FAN J,KIM S H.“Soft docking”:Matching of molecular surface cubes[J].J Mol Biol,1991,219(1):79-102.
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[30]LINDAHL E,HESS B,VAN DER SPOEL D.Gromacs 3.0:A package for molecular simulation and trajectory analysis[J].J Mol Mod,2001,7:306-317.
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[37]LASKOWSKI R A,MOSS D S,THORNTON J M.Main-chain bond lengths and bond angles in protein structures[J].J Mol Biol,1993,231:1049-1067.
[38]VRIEND G,SANDER C.Quality-control of protein models—directional atomic contact analysis[J].J Appl Cryst,1993,26:47-60.
[39]COL0V0S C,YEATES T O.Verification of protein structures:patterns of nonbonded atomic interactions[J].Protein Sci,1993,2:1511-1519.
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[41]BERNSTEIN B E,T0NG J K,SCHREIBER S L.Genomewide studies of histone deacetylase function in yeast[J].Proc Natl Acad Sci USA,2000,97:13708-13713.
[42]SINGH S B,ZINK D L,P0LISH00K J D,et al.Apicidins:Novel Cyclic Tetrapeptides as Coccidiostats and Antimalarial Agents from Fusarium pallidoroseum[J].Tetrahedron Lett,1996,37:8077-8080.
[43]DARKIN-RATTRAY S J,GURNETT A M,MYERS R W,et al.Apicidin:A novel antiprotozoal agent that inhibits parasite histone deacetylase[J].Proc Natl Acad Sci USA,1996,93:13143-13147.
[44]RODRIQUEZ M,TERRACCIANO S,CINI E,et al.Total synthesis,NMR solution structure,and binding model of the potent histone deacetylase inhibitor FR235222[J].Angew Chem Int Ed,2006,118:437-441.
[45]ROBERTS B C,MANCERA R L.Ligand-Protein Docking with Water Molecules[J].J Chem Inf Model,2008,48:397-408.
[46]GRAAF D C,P0SPISIL P,P0S W,et al.Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking[J].J Med Chem,2005,48:2308-2318.
[47]COLLETTI S L,MYERS R W,DARKIN-RATTRAY S J,et al.Broad spectrum antiprotozoal agents that inhibit histone deacetylase:structureactivity relationships of apicidin[J].Bioorg Med Chem Lett,2001,11:113-117.
[48]YAN C L,XIU Z L,LI X H,et al.Comparative molecular dynamics simulations of histone deacetylase-like protein:Binding modes and free energy analysis to hydroxamic acid inhibitors[J].Proteins,2008,73:134-149.
[49]ITO Y,KONDO H,GOLDFARB P S,et al.Analysis of CYP2D6 substrate interactions by computational methods[J].J Mol Graph Model,2008,26:947-956.
[50]SCHUETTELKOPF A W,VAN AALTEN D M F.PRODRG-a tool for high-throughput crystallography of protein-ligand complexes[J].Acta Crystallographica,2004,60:1355-1363.
[51]BERENDSEN H J C,POSTMA J P M,N0LA D A,et al.Molecular dynamics with coupling to an ext ernal bath[J].J Chem Phys,1984,81:3684-3690.
[52]DARDEN T,YORK D,PEDERSEN L.Particle mesh Ewald:an N log(N)method for Ewald sums in large systems[J].J Chem Phys,1993,98:10089-10092.
[2]李晓晖,李建勋,李世荣等.环肽类组蛋白去乙酰化酶抑制剂[J].化学进展,2007,19(05):762-168.
[3]PENNISI E.Opening the way to gene activity[J].Science,1997,275(5297):155-157.
[4]KURDISTANI S K,GRUNSTEIN M.Histone acetylation and deacetylation in yeast[J].Nat Rev Mol Cell Biol,2003,4:276-284.
[5]JESSICA E,BOLDEN,MELISSA J,et al.Anticancer activities of histone deacetylase inhibitors[J].Nat Rev Drug Discov,2006,5(9):769-784.
[6]王欣,刘丹,吕金玲等.组蛋白去乙酰化酶抑制剂的研究进展[J].中国药物化学杂志,2006,16(5):316-322.
[7]PARIS M,PORCELLONI M,BINASCHI M,et al.Histone deacetylase inhibitors:from bench to clinic[J].J Med them,2008,51:1505-1529.
[8]ANNEMIEKE J M,DE R,ALBERT H,et al.Histone deacetylases(HDACs):characterization of the classical HDAC family[J].Biochem J,2003,370(3):737-749.
[9]FINNIN M S,DONIGIAN J R,COHEN A,et al.Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors[J].Nature,1999,401(6749):188-193.
[10]VANNINI A,VOLPARI C,FILOCAMO G,et al.Crystal structure of a eukaryotic zinc-dependent histone deacetylase,human HDAC8,complexed with a hydroxamic acid inhibitor[J].Proc Natl Acad Sci USA,2004,101:15064-15069.
[11]SOMOZA J R,SKENE R J,KATZ B A,et al.Structural snapshots of human HDAC8 provide insight into class I histone deacetylases[J].Structure,2004,12:1325-1334.
[12]NIELSEN T K,HILDMANN C,DICKMANNS A,et al.Crystal structure of a bacterial class 2 histone deacetylase homologue[J].J Mol Biol,2005,354:107-120.
[13]MARKS P A,RICHON V M,RIFKIND R A.Histone deacetylase inhibitors:inducers of differentiation or apoptosis of transformed cells[J].J Natl Cancer Inst,2000,92(15):1210-1216.
[14]JONESTONE R W.Histone-deacetylase inhibitors:novel drugs for the treatment of cancer [J].Nat rev Drug discov,2002,1(1):287-299.
[15]WANG D F,WIEST O G,HELQUIST P,et al.On the function of the 14(?) long internal cavity of histone deacetylase like protein:implications for the design of histone deacetylase inhibitors[J].J Med Chem,2004,47:3409-3417.
[16]WANG D F,HELQUIST P,WIECH N L,et al.Toward Selective Histone Deacetylase Inhibitor Design:Homology Modeling,Docking Studies,and Molecular Dynamics Simulations of Human Class I Histone Deacetylases[J].J Med Chem,2005,48:6936-6947.
[17]RODRIQUEZ M,TERRACCIANO S,CINI E,et al.Total Synthesis,NMR Solution Structure,and Binding Model of the Potent Histone Deacetylase Inhibitor FR235222[J].Angew Chem Int Ed,2006,45(3):423-427.
[18]MAULUCCI N,CHINI M G,MICCO D S,et al.Molecular Insights into Azumamide E Histone Deacetylases Inhibitory Activity[J].J Am Chem Soc,2007,129:3007-3012.
[19]闫春丽.蛋白和配体相互作用的分子动力学模拟与分析[D]:(博士学位论文).大连:大连理工大学,2008.
[20]WILKINS M R,SANCHEZ J C,GOOLEY A A,et al.Progress with proteome projects:why all proteins expressed by a genome should be identified and how to do it[J].Biotechnol Genet Eng Rev,1996,13:19-50.
[21]GUIDA W C.Software for structure-based drug design[J].Curr Opin Struc Biol,1994,4:777-781.
[22]BERMANH H M,WESTBROOK J,FENGZ,et al.The Protein Data Bank[J].Nucleic Acids Res,2000,28:235-242.
[23]尹海滨.生长抑素受体3D 结构的同源模建及其配体固相合成研究[D]:(博士学位论文).成都:四川大学,2007.
[24]FISER A,SALI A.MODELLER:generation and refinement of homology-based protein structure models[J].Methods Enzymol,2003,374:463-493.
[25]T.伦盖威尔.生物信息学——从基因组到药物[M].郑珩,王非译.北京:化学工业出版社,2006.
[26]FAN J,KIM S H.“Soft docking”:Matching of molecular surface cubes[J].J Mol Biol,1991,219(1):79-102.
[27]陈凯先,蒋华良,嵇汝运.计算机辅助药物设计——原理、方法及应用[M].上海:上海科学技术出版社,2000.
[28]MORRIS G M,GOODSELL D S,HALLIDAY R S,et al.Automated Docking Using a Lamarckian Genetic Algorithm and and Empirical Binding Free Energy Function[J].J Comput Chem,1998,19:1639-1662.
[29]HUEY R,MORRIS M G,OLSON A J,et al.A semiempirical free energy force field with charge-based desolvation[J].J Comput Chem,2007,28(6):1145-1152.
[30]LINDAHL E,HESS B,VAN DER SPOEL D.Gromacs 3.0:A package for molecular simulation and trajectory analysis[J].J Mol Mod,2001,7:306-317.
[31]VAN DER SPOEL D,LINDAHL E,HESS B,et al.Gromacs User Manual version 3.2.2004.http://www.gromacs.org.
[32]BURKERT U,ALLINGER N L.Molecular mechanics[M],ACS Monograph 177.Washington D.C:American Chemical Society,1982.
[33]LEVITT M,LIFSON S.Refinement of protein conformations using a macromolecular energy minimization procedure[J].J Mol Biol,1969,46(1):269-279.
[34]FLECHER R,REEVES C M.Function minimization by conjugate gradients[J].The Computer Journal,1964,7(2):149-154.
[35]VAN GUNSTEREN W F,KARPLUS M.A method for constrained energy minimization of macromolecules[J].Journal of Computational Chemistry,1980,1(3):266-274.
[36]FLECHER R.A new approach to variable metric algorithms[J].Comput J,1970,13(3):317-322.
[37]LASKOWSKI R A,MOSS D S,THORNTON J M.Main-chain bond lengths and bond angles in protein structures[J].J Mol Biol,1993,231:1049-1067.
[38]VRIEND G,SANDER C.Quality-control of protein models—directional atomic contact analysis[J].J Appl Cryst,1993,26:47-60.
[39]COL0V0S C,YEATES T O.Verification of protein structures:patterns of nonbonded atomic interactions[J].Protein Sci,1993,2:1511-1519.
[40]THOMPSON J D,HIGGINS D G,GIBSON T J.CLUSTAL W:improving the sensitivity of progressive multiple sequence alignment through sequence weighting,positions-specific gap penalties and weight matrix choice[J].Nucleic Acids Res,1994,22:4673-4680.
[41]BERNSTEIN B E,T0NG J K,SCHREIBER S L.Genomewide studies of histone deacetylase function in yeast[J].Proc Natl Acad Sci USA,2000,97:13708-13713.
[42]SINGH S B,ZINK D L,P0LISH00K J D,et al.Apicidins:Novel Cyclic Tetrapeptides as Coccidiostats and Antimalarial Agents from Fusarium pallidoroseum[J].Tetrahedron Lett,1996,37:8077-8080.
[43]DARKIN-RATTRAY S J,GURNETT A M,MYERS R W,et al.Apicidin:A novel antiprotozoal agent that inhibits parasite histone deacetylase[J].Proc Natl Acad Sci USA,1996,93:13143-13147.
[44]RODRIQUEZ M,TERRACCIANO S,CINI E,et al.Total synthesis,NMR solution structure,and binding model of the potent histone deacetylase inhibitor FR235222[J].Angew Chem Int Ed,2006,118:437-441.
[45]ROBERTS B C,MANCERA R L.Ligand-Protein Docking with Water Molecules[J].J Chem Inf Model,2008,48:397-408.
[46]GRAAF D C,P0SPISIL P,P0S W,et al.Binding mode prediction of cytochrome P450 and thymidine kinase protein-ligand complexes by consideration of water and rescoring in automated docking[J].J Med Chem,2005,48:2308-2318.
[47]COLLETTI S L,MYERS R W,DARKIN-RATTRAY S J,et al.Broad spectrum antiprotozoal agents that inhibit histone deacetylase:structureactivity relationships of apicidin[J].Bioorg Med Chem Lett,2001,11:113-117.
[48]YAN C L,XIU Z L,LI X H,et al.Comparative molecular dynamics simulations of histone deacetylase-like protein:Binding modes and free energy analysis to hydroxamic acid inhibitors[J].Proteins,2008,73:134-149.
[49]ITO Y,KONDO H,GOLDFARB P S,et al.Analysis of CYP2D6 substrate interactions by computational methods[J].J Mol Graph Model,2008,26:947-956.
[50]SCHUETTELKOPF A W,VAN AALTEN D M F.PRODRG-a tool for high-throughput crystallography of protein-ligand complexes[J].Acta Crystallographica,2004,60:1355-1363.
[51]BERENDSEN H J C,POSTMA J P M,N0LA D A,et al.Molecular dynamics with coupling to an ext ernal bath[J].J Chem Phys,1984,81:3684-3690.
[52]DARDEN T,YORK D,PEDERSEN L.Particle mesh Ewald:an N log(N)method for Ewald sums in large systems[J].J Chem Phys,1993,98:10089-10092.