联芳基氨基噻嗪类BACE1抑制剂的3D-QSAR分析与分子对接研究
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摘要
目的:为新型高效联芳基氨基噻嗪类β-淀粉样前体蛋白水解酶1(BACE1)抑制剂的设计合成与新型AD治疗药物研发提供理论基础。方法:选取41个联芳基氨基噻嗪类BACE1抑制剂分子,运用SYBYL-X 2.0软件包,以比较分子场分析法(CoMFA)与比较分子相似性指数分析法(CoMSIA)构建该类衍生化合物的三维定量构效关系(3D-QSAR)模型,并以Surflex-dock分子对接方法分析该类化合物与BACE1的结合模式。结果:以CoMFA法和CoMSIA法构建的3D-QSAR模型的交叉验证系数(q~2)均大于0.5,表明其预测能力良好;所建三维等势图能直观反映不同位置引入取代基对化合物活性的影响。Surflex-dock对接分析显示,联芳基氨基噻嗪类分子与BACE1中的ASP80、ASP276、TYR246等氨基酸残基具有氢键作用。结论:基于联芳基氨基噻嗪类衍生化合物所构建的3D-QSAR模型具有良好的预测能力,可指导该类化合物的结构优化;TYR246可能是联芳基氨基噻嗪类抑制剂化合物分子与BACE1结合的另一潜在活性功能残基。通过3D-QSAR分析与分子对接,可进行新型高效联芳基氨基噻嗪类BACE1抑制剂的设计合成,进而用于研发新型AD治疗药物。
OBJECTIVE:To provide theoretic basis for the design and synthesis of novel high-activity biaryl aminothiazine β-amyloid precursor protein cleaving enzyme 1(BACE1) inhibitor, the research and development of new AD therapy drugs.METHODS:Totally 41 molecules of biaryl aminothiazine BACE1 inhibitors were selected. By SYBYL-X 2.0 software package,CoMFA and CoMSIA method were used to construct 3D-QSAR model of derivatized compounds. Surflex-dock molecular docking was applied to analyze binding mode of the compounds with BACE1. RESULTS:The q~2 value of 3D-QSAR model established by CoMFA and CoMSIA method were all higher than 0.5,indicating good predictability. The established three dimensional contour plots could manifest the effect of substituents at different sites on activity of compounds. Surflex-dock analysis showed that biaryl aminothiazine and amino acid residues as ASP80,ASP276 and TYR246 in BACE1 had a key effect on hydrogen bonds.CONCLUSIONS: 3D-QSAR model established on the basis of biaryl aminothiazine derivatized compounds show good predictability,which provides guidance for the structure optimization of the compound. TYR246 may be another potential active functional residue of biaryl aminothiazine inhibitor compound molecule combined with BACE1. Through 3D-QSAR analysis and molecular docking,new biaryl aminothiazine BACE1 inhibitor can be designed and synthesized so as to research and develop new drugs for AD.
OBJECTIVE:To provide theoretic basis for the design and synthesis of novel high-activity biaryl aminothiazine β-amyloid precursor protein cleaving enzyme 1(BACE1) inhibitor, the research and development of new AD therapy drugs.METHODS:Totally 41 molecules of biaryl aminothiazine BACE1 inhibitors were selected. By SYBYL-X 2.0 software package,CoMFA and CoMSIA method were used to construct 3D-QSAR model of derivatized compounds. Surflex-dock molecular docking was applied to analyze binding mode of the compounds with BACE1. RESULTS:The q~2 value of 3D-QSAR model established by CoMFA and CoMSIA method were all higher than 0.5,indicating good predictability. The established three dimensional contour plots could manifest the effect of substituents at different sites on activity of compounds. Surflex-dock analysis showed that biaryl aminothiazine and amino acid residues as ASP80,ASP276 and TYR246 in BACE1 had a key effect on hydrogen bonds.CONCLUSIONS: 3D-QSAR model established on the basis of biaryl aminothiazine derivatized compounds show good predictability,which provides guidance for the structure optimization of the compound. TYR246 may be another potential active functional residue of biaryl aminothiazine inhibitor compound molecule combined with BACE1. Through 3D-QSAR analysis and molecular docking,new biaryl aminothiazine BACE1 inhibitor can be designed and synthesized so as to research and develop new drugs for AD.
引文
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[2]PRINCE M,GUERCHET M,PRINA M.The Global impact of dementia:2013-2050[R].Health Services&Population Research,2013.
[3]LV ZY,TAN CC,YU JT,et al.Spreading of pathology in Alzheimer’s disease[J].Neurotox Res,2017,32(4):707-722.
[4]MOORTHI V,PREETHI B.A review on Alzhimer’s disease:pathology,molecular conditions,managemnt and causes[J].Asian J Pharm Clin Res,2017,10(5):27.
[5]VASSAR R,KOVACS DM,YAN R,et al.Theβ-secretase enzyme BACE in health and Alzheimer’s disease:regulation,cell biology,function,and therapeutic potential[J].J Neurosci,2009,29(41):12787-12794.
[6]HUNT KW,COOK AW,WATTS RJ,et al.Spirocyclicβ-site amyloid precursor protein cleaving enzyme 1(BACE1)inhibitors:from hit to lowering of cerebrospinal fluid(CSF)amyloidβin a higher species[J].J Med Chem,2013,56(8):3379-3403.
[7]CHEN JJ,LIU Q,YUAN C,et al.Development of 2-aminooxazoline 3-azaxanthenes as orally efficaciousβ-secretase inhibitors for the potential treatment of Alzheimer’s disease[J].Bioorg Med Chem Lett,2015,25(4):767-774.
[8]MANDAL M,ZHU Z,CUMMING JN,et al.Design and validation of bicyclic iminopyrimidinones as beta amyloid cleaving enzyme-1(BACE1)inhibitors:conformational constraint to favor a bioactive conformation[J].J Med Chem,2012,55(21):9331-9345.
[9]MAY PC,DEAN RA,LOWE SL,et al.Robust central reduction of amyloid-βin humans with an orally available,non-peptidicβ-secretase inhibitor[J].J Neurosci,2011,31(46):16507-16516.
[10]WU YJ,JASON G,SHI JL,et al.Discovery of S3-truncated,C-6 heteroaryl substituted aminothiazineβ-site APP cleaving enzyme-1(BACE1)inhibitors[J].J Med Chem,2016,59(18):8593-8600.
[11]LI HN,LI FR,CHENG MS,et al.Advances on non-peptide BACE1 inhibitors[J].Chin J Med Chem,2016,26(6):498-508.
[12]PUTZ MV,DUDA?NA.Variational principles for mechanistic quantitative structure-activity relationship(QSAR)studies:application on uracil derivatives’anti-HIV action[J].Struct Chem,2013,24(6):1873-1893.
[13]SAMMI T,SILAKARI O,RAVIKUMAR M.Three-dimensional quantitative structure-activity relationship modeling of gamma-secretase inhibitors using molecular field analysis[J].Chem Biol Drug Des,2008,71(2):155-166.
[14]ENTEZARI HY,SERESHTI H,SABOURY AA,et al.3D QSAR studies,pharmacophore modeling,and virtual screening of diarylpyrazole-benzenesulfonamide derivatives as a template to obtain new inhibitors,using human carbonic anhydraseⅡas a model protein[J].J Enzym Inhib Med Chem,2017,32(1):688-700.
[15]XIE H,CHEN L,ZHANG J,et al.A combined pharmacophore modeling,3D QSAR and virtual screening studies on imidazopyridines as B-Raf inhibitors[J].Int J Mol Sci,2015,16(6):12307-12323.
[16]BORISA A,BHATT H.3D-QSAR(Co MFA,Co MFA-RG,Co MSIA)and molecular docking study of thienopyrimidine and thienopyridine derivatives to explore structural requirements for aurora-B kinase inhibition[J].Eur J Pharm Sci,2015,79:1-12.
[17]CHAUBE U,CHHATBAR D,BHATT H.3D-QSAR,molecular dynamics simulations and molecular docking studies of benzoxazepine moiety as m TOR inhibitor for the treatment of lung cancer[J].Bioorg Med Chem Lett,2016,26(3):864-874.
[18]WU YJ,GUERNON J,YANG F,et al.Targeting the BACE1 active site flap leads to a potent inhibitor that elicits robust brain Aβreduction in rodents[J].ACS Med Chem Lett,2016,7(3):271-276.
[19]WU YJ,GUERNON JM.4,6-diarylaminothiazines as BACE1 inhibitors and their use for the reduction of betaamyloid production,US:9475784B2[P].2016-10-25.
[20]PRATI F,BOTTEGONI G,BOLOGNESI ML,et al.BACE-1 inhibitors:from recent single-target molecules to multitarget compounds for Alzheimer’s disease[J].J Med Chem,2017,61(3):619-637.
[21]ZHENG S,ZHONG Q,XI Y,et al.Modification and biological evaluation of thiazole derivatives as novel inhibitors of metastatic cancer cell migration and invasion[J].J Med Chem,2014,57(15):6653-6667.
[22]XIE A,SIVAPRAKASAM P,DOERKSEN RJ.3D-QSAR analysis of antimalarial farnesyltransferase inhibitors based on a 2,5-diaminobenzophenone scaffold[J].Bioorgan Med Chem,2006,14(21):7311-7323.
[23]BUSH BL,JR RBN.Sample-distance partial least squares:PLS optimized for many variables,with application to Co MFA[J].J Comput Aid Mol Des,1993,7(5):587-619.
[24]MARELLA A,AKHTER M,SHAQUIQUZZAMAN M,et al.Synthesis,3D-QSAR and docking studies of pyrimidine nitrile-pyrazoline:a novel class of hybrid antimalarial agents[J].Med Chem Res,2014,24(3):1018-1037.
[25]ALMERICO AM,TUTONE M,LAURIA A.Receptorguided 3D-QSAR approach for the discovery of c-kit tyrosine kinase inhibitors[J].J Mol Model,2012,18(7):2885-2895.
[26]AKAMATSU M.Current state and perspectives of 3DQSAR[J].Curr Top Med Chem,2002,2(12):1381-1394.
[27]ZENG GH,FANG DQ,WU WJ,et al.Binding conformations,QSAR,and molecular design of alkene-3-quinolinecarbonitriles as Src inhibitors[J].Int J Quantum Chem,2013,113(10):1467-1478.