• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    多種類雜環(huán)化合物的藥理和毒理活性系數構效關系

    2014-09-17 06:59:58朱志臣賈青竹夏淑倩馬沛生
    物理化學學報 2014年6期
    關鍵詞:毒理青竹化工學院

    朱志臣 王 強 賈青竹 夏淑倩 馬沛生

    (1天津城建大學理學院,天津300384;2天津科技大學材料科學與化學工程學院,天津300457;3天津科技大學海洋科學與工程學院,天津300457;4天津大學化工學院,天津300072)

    1 Introduction

    Heterocyclic compounds are important as drugs.According to Hammond,1the most important objective of synthesis is not production of new compounds,but production of properties.And for the drug discovery process,the aim is at bringing to market new drugs with desirable pharmaco-dynamicity,and favorable ADMET(Absorption,Distribution,Metabolism,Elimination,and Toxicity)properties.2-5Therefore,drug designers and toxicologists pay much attention to the beneficial and deleterious effects of heterocyclic moieties in molecules.

    In view of the fact that most potential therapeutic agents and the majority of known drugs do not have experimental data available for their evaluation,theoretical calculations are very useful in the initial screening of compound libraries.Previous studies have demonstrated that quantitative structure-activity/property relationships(QSAR/QSPR)approach is successful in predicting activities,properties,and toxicities including mutagenicity(described as lnR)of aromatic and hetero-aromatic amines.6-12For example,the aryl hydrocarbon receptor binding affinity(described as pEC50)is well documented in the field of toxicology for organics.13-15Basak et al.16proposed a hierarchical quantitative structure-activity relationship(HiQSAR)approach for the pEC50prediction.According to their investigation,the topostructural(TS)and topochemical(TC)descriptors could provide a good model for the pEC50prediction with a r2value of 0.852.And with Basak et al.′smethod,the r2value is of 0.748 for lnR prediction.17In order to explore the binding mode and interaction mechanism between hydroxylated polychlorinated biphenyls and aryl hydrocarbon receptor,Cao et al.18proposed some comparative molecular similarity index analysis models by using molecular dynamics simulations.And their optimum 3D-QSAR model could show good predictive ability(r2=0.913)and good mechanism interpretability.

    Recently,a universal positional distributive contribution theory for the prediction of various properties of organic compounds was developed.19-21In this theory,the specific position of a group in the molecule was considered as the position factor.Here,the position factor was used to take into account longer distance interactions,which could distinguish the overall isomer including cis-and trans-or Z-and E-structures of organic compounds for their thermodynamics properties.Moreover,our previous works suggest that it is possible to use a totally same universal framework to predict the critical properties and the thermodynamics properties of organic compounds containing various functionalities.

    Very recently,a topological index was proposed based on atom characters(e.g.,atom radius and atom electronegativity etc.)by our research group,which has been successfully used for predicting the critical micelle concentration(CMC)of various surfactants,22the decomposition temperature,23toxicity of ionic liquids,24and the aquatic toxicity for various narcotic pollutants.25And,it is logical to see if this topological index could be used for prediction of pharmacological and toxicological activities of drugs.

    In this work,based on this topological index and through data mining,a universal model has been developed for prediction of the two different properties.The major objectives of this study are:(i)to propose a set of norm indexes,(ii)to establish a more general QSPR model for prediction of pharmacological and toxicological activities of heterocyclic compounds,and(iii)to compare the performance of our model with other methods.

    2 Methodology

    2.1 Pharmacological and toxicological activity data

    2.1.1 Aryl hydrocarbon(AH)receptor data

    In this work,a set of 32 dibenzofurans compounds(structure shown as in Fig.1)with AH receptor binding potency values obtained from the literature26were used for QSAR model development,and the experimental data are listed in Table S1(shown as Supporting Information).

    2.1.2 Mutagenicity of aromatic and heteroaromatic amines

    The set of 95 aromatic and heteroaromatic amines used to study mutagenic potency(described as lnR)was obtained from Debnath et al.,27and their experimental mutation rates are listed in Table S2(shown as Supporting Information).

    2.2 Proposed method

    In our previous work,22the extended adjacency matrix MA,the extended interval matrix MB,the extended interval jump matrix MC,and extended distance matrix MDare defined,respectively.

    The constituents of the distance matrix Mdand the extended matrix,Me,are described as follows.

    Md=(aij),distance matrix aij=n

    (if the path length between the atoms i and j is n)

    Fig.1 Structure for the dibenzofuran data set provided in Table S1

    Here,as for MA,MB,MC,and MD,a set of norm indexes have been proposed as follows.

    where norm(MA,1)means the largest column sum of matrix MA,norm(MA,2)means the largest singular value of matrix MA,norm(MA,fro)is the frobenius-norm of matrix MA,and norm(MA,inf)is the infinite-norm of matrix MA.

    Using these norm indexes,two QSPR models for pEC50and lnR prediction are expressed as Eq.(1)and Eq.(2).The modeling work is performed with ordinary least squares regression.

    Here,N for total number of atoms,MWis molecular weight,M0is the constant added.As for parameters a,b1,b2,and M0,the regression results for prediction of pEC50and lnR are summarized in Table 1.

    Some statistical metrics for our predictive models are as follows.PRESS stands for the predicted sum of squared error,AD stands for the absolute difference,RD means relative deviation,andAAD is the average absolute difference.

    Table 1 Parameters for prediction of pEC50and lnR

    3 Results and discussions

    3.1 pEC50prediction results

    The pEC50prediction results are provided in Table S1(shown as Supporting Information),along with the differences between the experimental and predicted values.The calculated by model Eq.(1)vs experimental pEC50scatter plot for this regression is presented in Fig.2(a).And statistical metrics for the predictive model are listed in Table 2.The results in Fig.2(a)indicate that the predicted pEC50agree well with the“experimental results”.The AAD for pEC50prediction of 32 dibenzofurans compounds is 0.403.Also,our high-quality prediction model is evidenced by a r2value of 0.876 and a PRESS value of 7.734.

    3.2 lnR prediction results

    The lnR prediction results are provided in Table S2,Table 2,and Fig.2(b).Results indicate that our new model Eq.(2)for predicting lnR has good overall accuracy.The AAD for lnR prediction of 95 aromatic and heteroaromatic amines is 0.702,the r2value is 0.779,and the PRESS value is 80.3.

    3.3 Comparison with the HiQSAR approach

    The pEC50prediction results with the HiQSAR approach proposed by Basak et al.16had been used for comparison,and the comparison results are also provided in Table S1 and Table 2.According to Basak et al.,16the topostructural(TS)and topochemical(TC)descriptors could provide a good model for the pEC50prediction with a r2value of 0.852.Using their method,the AAD for pEC50prediction is 0.452,and the PRESS value is 9.270.In addition,with the method of Basak et al.,17the AAD for lnR prediction is 0.747,the r2value is of 0.748,and the PRESS value is 87.6.Comparison results therefore indicate that obvious improvement could be obtained with our method.

    In Basak et al.′sresearch,prediction for pEC50and lnR of organic compounds was based on about 72 or even more optimal descriptors which had been selected from 300 descriptors.Moreover,in their work,the number of descriptors is large with respect to the number of chemical compounds in the data set,so the ordinary least-square regression is inappropriate.

    Fig.2 Scatter plot showing the correlation between predicted by our models and experimental pEC50(a)and lnR(b)

    Table 2 Regression results for prediction of pEC50and lnR based on our models and Basak et al.′smethod

    While,in our work,based on the extended distance matrix,a set of norm indexes have been proposed.By using these norm indexes,the structure and the composition of molecules could be determined stably,accurately,and completely,and also,the isomers could be distinguished well.Moreover,it should be strongly stated that firstly,only 17 indices are considered for property prediction of chemical compounds,among which 14 indices are deduced from these norm indexes.Secondly and more importantly,a totally same mathematical model is developed for predicting pEC50and lnR of organic compounds containing various functionalities with better prediction performance.

    Therefore,it could be demonstrated that our method with these norm indexes could result in significant improvement both in accuracy and generality for predicting pEC50and lnR.Also,owing to the much less variables considered,this algorithm could perform well in the ductility,which is very important and particularly valuable for a prediction method.

    3.4 Leave-one-out cross-validation

    In this work,the leave-one-out algorithm was used for the validation of the prediction of our QSPR models,and results are also shown in Table 3.Results show that the r2and PRESS are acceptable and they are as good as the results calculated by Eq.(1)and Eq.(2).The calculated values by leave-one-out crossvalidation demonstrate that our QSPR models Eq.(1)and Eq.(2)based on these norm indexes have good predictive stability and reliability for predicting the pEC50and lnR.

    Table 3 Regression results for prediction of pEC50and lnR based on our model and predicting ability test by leave-one-out cross-validation

    4 Conclusions

    In this work,a set of norm indexes for predicting the AH receptor prediction(pEC50)of 32 dibenzofurans and the mutagenic potency lnR of 95 aromatic and heteroaromatic amines was proposed.Based on these norm index,a totally same mathematical model was developed for predicting pEC50and lnR of organic compounds containing various functionalities.Results indicated that pEC50and lnR were successfully predicted with a significant degree of confidence.With our method,the AAD values for pEC50prediction and lnR prediction are 0.403 and 0.702,r2values are of 0.876 and 0.779,respectively.Also,this research provides better prediction results as compared to the HiQSAR method of Basak et al.,despite the fact that lesser descriptors were considered and used in this research as compared to other models.Moreover,our results demonstrated that it is possible to use a totally same mathematical model for predicting pEC50and lnR of organic compounds containing various functionalities with better prediction performance.

    Supporting Information: Experimental and predicted the aryl hydrocarbon(AH)receptor binding affinity(pEC50)of dibenzofurans and the mutagenic potency lnR of aromatic and heteroaromatic amines based on this model and Basak et al.′smethod,and a detailed procedure for the pEC50estimation have been included.This information is available free of charge via the internet at http://www.whxb.pku.edu.cn.

    (1)Hammond,G.S.NorrisAward Lecture,1968.

    (2) Michielan,L.;Moro,S.J.Chem.Inf.Model.2010,50,961.doi:10.1021/ci100072z

    (3) Khan,M.T.;Sylte,I.Curr.Drug Discovery Technol.2007,4,141.doi:10.2174/157016307782109706

    (4) Mager,D.E.Adv.Drug Delivery Rev.2006,58,1326.doi:10.1016/j.addr.2006.08.002

    (5) Zhu,H.;Tropsha,A.;Fourches,D.;Varnek,A.;Papa,E.;Gramatica,P.;Oberg,T.;Dao,P.;Cherkasov,A.;Tetko,I.V.J.Chem.Inf.Model.2008,48,766.doi:10.1021/ci700443v

    (6) Basak,S.C.;Mills,D.SAR QSAR Environ.Res.2001,12,481.doi:10.1080/10629360108039830

    (7) Gute,B.D.;Balasubramanian,K.;Geiss,K.T.;Basak,S.C.Environ Toxicol Pharmacol,2004,16,121.

    (8) Restrepo,G.;Basak,S.C.;Mills,D.Curr.Comput.Aided Drug Des.2011,7,109.doi:10.2174/157340911795677639

    (9) Basak,S.C.;Mills,D.R.;Balaban,A.T.;Gute,B.D.J.Chem.Inf.Comput.Sci.2001,41,671.doi:10.1021/ci000126f

    (10) Godavarthy,S.S.;Robinson,R.L.,Jr.;Gasem,K.A.M.Fluid Phase Equilib.2008,264,122.doi:10.1016/j.fluid.2007.11.003

    (11) Basak,S.C.;Mills,D.;Gute,B.D.;Natarajan,R.Top Heterocycl.Chem.2006,3,39.

    (12)Li,X.L.;Ye,L.;Wang,X.X.;Wang,X.Z.;Liu,H.L.;Qian,X.P.;Zhu,Y.L.;Yu,H.X.Sci.Total Environ.2012,441,230.doi:10.1016/j.scitotenv.2012.08.072

    (13) Doering,J.A.;Wiseman,S.;Beitel,S.C.;Giesy,J.P.;Hecker,M.Aquat.Toxicol.2014,150,27.doi:10.1016/j.aquatox.2014.02.009

    (14)Gu,C.;Goodarzi,M.;Yang,X.;Bian,Y.;Sun,C.;Jiang,X.Toxicol.Lett.2012,208,269.

    (15) Hankinson,O.Arch.Biochem.Biophys.2005,433,379.doi:10.1016/j.abb.2004.09.031

    (16)Basak,S.C.;Mills,D.;Mumtaz,M.M.;Balasubramanian,K.Indian J.Chem.2003,42A,1385.

    (17) Basak,S.C.;Mills,D.;Gute,B.D.;Hawkins,D.M.Predicting Mutagenicity of Congeneric and DiverseSets of Chemicals Using Computed Molecular Descriptors:a Hierarchical Approach.In Benigni R(ed)Quantitative Structure-Activity Relationship(QSAR)Models of Mutagens and Carcinogens;CRC:Boca Raton,FL,2003;pp 207-208.

    (18) Cao,F.;Li,X.;Ye,L.;Xie,Y.;Wang,X.;Shi,W.;Qian,X.;Zhu,Y.;Yu,H.Environ.Toxicol.Pharmacol.2013,36,626.doi:10.1016/j.etap.2013.06.004

    (19)Wang,Q.;Ma,P.S.;Jia,Q.Z.;Xia,S.Q.J.Chem.Eng.Data 2008,53,1103.doi:10.1021/je700641j

    (20)Wang,Q.;Jia,Q.Z.;Ma,P.S.J.Chem.Eng.Data 2012,57,169.doi:10.1021/je200971z

    (21) Jia,Q.Z.;Wang,Q.;Ma,P.S.;Xia,S.Q.;Yan,F.Y.;Tang,H.M.J.Chem.Eng.Data 2012,57,3357.doi:10.1021/je301070f

    (22)Zhu,Z.C.;Wang,Q.;Jia,Q.Z.;Tang,H.M.;Ma,P.S.Acta Phys.-Chim.Sin.2013,29(1),30.[朱志臣,王 強,賈青竹,湯紅梅,馬沛生.物理化學學報,2013,29(1),30.]doi:10.3866/PKU.WHXB201210265

    (23)Yan,F.;Xia,S.;Wang,Q.;Ma,P.S.J.Chem.Eng.Data 2012,57,805.doi:10.1021/je201023a

    (24)Yan,F.;Xia,S.;Wang,Q.;Ma,P.S.J.Chem.Eng.Data 2012,57,2252.doi:10.1021/je3002046

    (25)Wang,Q.;Jia,Q.Z.;Yan,L.H.;Ma,P.S.;Xia,S.Q.doi:10.1016/j.chemosphere.2014.02.030

    (26) So,S.S.;Karplus,M.J.Med.Chem.1997,40,4360.

    (27)Debnath,A.K.;Debnath,G.;Shusterman,A.J.;Hansch,C.A.Environ.Mol.Mutagen.1992,19,37.doi:10.1002/em.2850190107

    猜你喜歡
    毒理青竹化工學院
    使固態(tài)化學反應100%完成的方法
    淡雅青竹,留韻傳芳
    國家開放大學石油和化工學院學習中心列表
    【鏈接】國家開放大學石油和化工學院學習中心(第四批)名單
    傳承,讓留青竹刻發(fā)揚光大
    華人時刊(2020年23期)2020-04-13 06:04:04
    《化工學報》贊助單位
    化工學報(2016年3期)2016-03-14 08:37:00
    青竹小鎮(zhèn)
    納米金的生殖毒理研究進展和展望
    汽車行業(yè)產銷數據
    汽車縱橫(2012年11期)2012-04-29 11:47:39
    《中國藥理學與毒理學雜志》毒理學專輯征稿通知
    av在线老鸭窝| 日韩中文字幕欧美一区二区 | 在线 av 中文字幕| 一本一本久久a久久精品综合妖精| 欧美 亚洲 国产 日韩一| 亚洲伊人色综图| 1024香蕉在线观看| 久久人人爽av亚洲精品天堂| 久久亚洲国产成人精品v| 女警被强在线播放| 伊人久久大香线蕉亚洲五| 热re99久久国产66热| 99热国产这里只有精品6| 亚洲成人免费电影在线观看 | 国产真人三级小视频在线观看| 精品少妇久久久久久888优播| 大香蕉久久网| 麻豆乱淫一区二区| 亚洲av日韩精品久久久久久密 | 久久久国产精品麻豆| 久久久久久久久久久久大奶| 男人添女人高潮全过程视频| 国产男女内射视频| 午夜福利乱码中文字幕| 成人影院久久| 国产在线观看jvid| 亚洲欧美清纯卡通| 十分钟在线观看高清视频www| 中国美女看黄片| 精品亚洲乱码少妇综合久久| www.自偷自拍.com| 人成视频在线观看免费观看| 国产片特级美女逼逼视频| 久久久亚洲精品成人影院| 欧美变态另类bdsm刘玥| 一级黄色大片毛片| 久久这里只有精品19| 午夜福利乱码中文字幕| 99国产精品一区二区三区| 一级毛片 在线播放| 亚洲黑人精品在线| 19禁男女啪啪无遮挡网站| 侵犯人妻中文字幕一二三四区| 国产男女内射视频| 精品免费久久久久久久清纯 | 欧美精品亚洲一区二区| 国产视频首页在线观看| 久久久精品国产亚洲av高清涩受| 国产三级黄色录像| 日韩电影二区| 婷婷色av中文字幕| 日日摸夜夜添夜夜爱| 极品人妻少妇av视频| 亚洲国产精品一区二区三区在线| 欧美av亚洲av综合av国产av| 国产精品熟女久久久久浪| 国产精品欧美亚洲77777| 高潮久久久久久久久久久不卡| 看免费成人av毛片| 成人影院久久| 国产老妇伦熟女老妇高清| 色视频在线一区二区三区| 后天国语完整版免费观看| 少妇精品久久久久久久| 国产精品人妻久久久影院| 日本欧美视频一区| 色精品久久人妻99蜜桃| 日韩 亚洲 欧美在线| 免费看不卡的av| 中文乱码字字幕精品一区二区三区| 国产不卡av网站在线观看| 99九九在线精品视频| 亚洲一区二区三区欧美精品| 一边摸一边抽搐一进一出视频| 午夜福利一区二区在线看| 视频区图区小说| 国产欧美日韩一区二区三 | 脱女人内裤的视频| 少妇人妻 视频| 热99久久久久精品小说推荐| 亚洲少妇的诱惑av| 中文字幕av电影在线播放| 又大又黄又爽视频免费| 天天操日日干夜夜撸| 亚洲国产精品999| 中文字幕亚洲精品专区| 亚洲中文字幕日韩| 天天躁日日躁夜夜躁夜夜| 精品一区二区三区四区五区乱码 | 国产精品香港三级国产av潘金莲 | 欧美精品高潮呻吟av久久| 久久精品国产综合久久久| 久久天堂一区二区三区四区| 韩国高清视频一区二区三区| 亚洲自偷自拍图片 自拍| 在线观看国产h片| 中文字幕另类日韩欧美亚洲嫩草| 日本av手机在线免费观看| 最新在线观看一区二区三区 | 成人三级做爰电影| 免费在线观看完整版高清| 久久久久久久大尺度免费视频| 我的亚洲天堂| 久久久国产一区二区| 最新在线观看一区二区三区 | 亚洲精品中文字幕在线视频| 男女边吃奶边做爰视频| 观看av在线不卡| 一级,二级,三级黄色视频| 捣出白浆h1v1| 亚洲国产精品国产精品| 欧美日韩精品网址| 精品第一国产精品| 亚洲av成人精品一二三区| 久久亚洲国产成人精品v| 三上悠亚av全集在线观看| xxx大片免费视频| 制服诱惑二区| 久久久久精品人妻al黑| 午夜免费成人在线视频| netflix在线观看网站| 免费久久久久久久精品成人欧美视频| 一区二区三区精品91| 老司机影院毛片| 日韩 欧美 亚洲 中文字幕| 亚洲欧美一区二区三区国产| 制服人妻中文乱码| 国产黄频视频在线观看| 男女免费视频国产| 巨乳人妻的诱惑在线观看| 日韩制服丝袜自拍偷拍| 国产日韩欧美视频二区| 亚洲国产最新在线播放| 日韩中文字幕视频在线看片| 国产黄色免费在线视频| 国产一区二区激情短视频 | 亚洲精品国产av成人精品| 国产精品一区二区在线不卡| 亚洲九九香蕉| 午夜福利乱码中文字幕| 啦啦啦啦在线视频资源| 少妇人妻久久综合中文| avwww免费| 国产精品熟女久久久久浪| 女警被强在线播放| 狠狠婷婷综合久久久久久88av| 黄片小视频在线播放| 欧美av亚洲av综合av国产av| 亚洲中文字幕日韩| 99国产精品一区二区三区| 最黄视频免费看| 最近中文字幕2019免费版| 国产免费又黄又爽又色| 久久久精品区二区三区| 亚洲国产最新在线播放| 国产激情久久老熟女| 久久九九热精品免费| 捣出白浆h1v1| 亚洲国产毛片av蜜桃av| 一区二区三区乱码不卡18| 亚洲成国产人片在线观看| 免费高清在线观看视频在线观看| 欧美激情极品国产一区二区三区| 亚洲精品成人av观看孕妇| 久久久久久久久久久久大奶| 国产成人精品久久久久久| 极品少妇高潮喷水抽搐| 亚洲av在线观看美女高潮| 乱人伦中国视频| 又紧又爽又黄一区二区| 免费在线观看影片大全网站 | 黑人巨大精品欧美一区二区蜜桃| 一区二区日韩欧美中文字幕| 久久av网站| 色精品久久人妻99蜜桃| 欧美日韩亚洲国产一区二区在线观看 | 亚洲伊人色综图| 蜜桃在线观看..| 色网站视频免费| 99香蕉大伊视频| 一级片'在线观看视频| 中文字幕色久视频| 亚洲欧洲日产国产| 视频在线观看一区二区三区| 日韩视频在线欧美| 性少妇av在线| 永久免费av网站大全| 丝袜美腿诱惑在线| 日韩欧美一区视频在线观看| 久久久国产欧美日韩av| 欧美成人午夜精品| 九色亚洲精品在线播放| 侵犯人妻中文字幕一二三四区| 黑人巨大精品欧美一区二区蜜桃| 国产亚洲精品第一综合不卡| 蜜桃国产av成人99| 老司机靠b影院| 久久久久久久大尺度免费视频| 好男人视频免费观看在线| 国产精品一区二区免费欧美 | 高清不卡的av网站| 亚洲 欧美一区二区三区| 一本大道久久a久久精品| 午夜福利影视在线免费观看| 多毛熟女@视频| 欧美黄色淫秽网站| 精品熟女少妇八av免费久了| 少妇裸体淫交视频免费看高清 | bbb黄色大片| 精品少妇久久久久久888优播| 曰老女人黄片| 在线看a的网站| 丝袜美足系列| 亚洲色图 男人天堂 中文字幕| 国产免费又黄又爽又色| 咕卡用的链子| 国产成人av教育| 久久天堂一区二区三区四区| 亚洲国产av影院在线观看| 一区福利在线观看| 高潮久久久久久久久久久不卡| 宅男免费午夜| 丰满少妇做爰视频| 母亲3免费完整高清在线观看| 久久狼人影院| 一级毛片我不卡| 国产精品秋霞免费鲁丝片| 99国产综合亚洲精品| 日韩 欧美 亚洲 中文字幕| 成人国产av品久久久| 日本午夜av视频| 亚洲精品中文字幕在线视频| 欧美久久黑人一区二区| 肉色欧美久久久久久久蜜桃| 亚洲欧美中文字幕日韩二区| 欧美另类一区| 菩萨蛮人人尽说江南好唐韦庄| 女性生殖器流出的白浆| 精品第一国产精品| 日本一区二区免费在线视频| 亚洲成色77777| 欧美在线黄色| 欧美精品啪啪一区二区三区 | 99热全是精品| 99香蕉大伊视频| 男女床上黄色一级片免费看| 国产精品久久久久久精品电影小说| 熟女少妇亚洲综合色aaa.| 成人免费观看视频高清| 国产在线观看jvid| 蜜桃国产av成人99| 国产精品久久久久久人妻精品电影 | 亚洲国产中文字幕在线视频| 精品久久久久久久毛片微露脸 | 亚洲欧美精品自产自拍| 岛国毛片在线播放| 国产在线视频一区二区| 欧美人与善性xxx| 亚洲国产看品久久| 搡老乐熟女国产| 女警被强在线播放| 日本色播在线视频| 免费观看a级毛片全部| 人人妻人人澡人人看| 久久精品成人免费网站| 你懂的网址亚洲精品在线观看| 新久久久久国产一级毛片| 久久久久久人人人人人| 人人妻,人人澡人人爽秒播 | 久久女婷五月综合色啪小说| 亚洲成国产人片在线观看| 热re99久久国产66热| 国产在线一区二区三区精| 久久久国产精品麻豆| 日本午夜av视频| 久久精品久久精品一区二区三区| 国产日韩欧美视频二区| 欧美av亚洲av综合av国产av| 欧美老熟妇乱子伦牲交| 亚洲中文av在线| 男的添女的下面高潮视频| 亚洲一区二区三区欧美精品| 在线观看免费午夜福利视频| 桃花免费在线播放| 久久青草综合色| 欧美 亚洲 国产 日韩一| 一级黄片播放器| 精品国产一区二区三区四区第35| 99国产综合亚洲精品| 两人在一起打扑克的视频| 真人做人爱边吃奶动态| 亚洲专区中文字幕在线| 亚洲人成网站在线观看播放| 嫁个100分男人电影在线观看 | 久久久久久人人人人人| 免费在线观看完整版高清| 欧美日韩成人在线一区二区| av国产精品久久久久影院| 亚洲国产精品国产精品| 国产av精品麻豆| 电影成人av| 国产精品成人在线| 欧美日韩亚洲国产一区二区在线观看 | 欧美+亚洲+日韩+国产| 国产又色又爽无遮挡免| 久久人妻熟女aⅴ| 国产成人欧美在线观看 | 亚洲国产欧美网| 亚洲少妇的诱惑av| 亚洲精品乱久久久久久| 国产男人的电影天堂91| 一边摸一边抽搐一进一出视频| 欧美黑人精品巨大| 久久天躁狠狠躁夜夜2o2o | 国产老妇伦熟女老妇高清| 热99久久久久精品小说推荐| 最近中文字幕2019免费版| 别揉我奶头~嗯~啊~动态视频 | 成年女人毛片免费观看观看9 | 少妇的丰满在线观看| 日韩免费高清中文字幕av| 日本五十路高清| 欧美日韩亚洲综合一区二区三区_| 十分钟在线观看高清视频www| 亚洲欧美精品综合一区二区三区| 十八禁高潮呻吟视频| 久久人妻福利社区极品人妻图片 | 亚洲三区欧美一区| 欧美日本中文国产一区发布| 国产熟女午夜一区二区三区| 精品少妇内射三级| av天堂在线播放| 国产成人精品在线电影| 免费高清在线观看视频在线观看| 久久久久精品国产欧美久久久 | 大片电影免费在线观看免费| 亚洲一区中文字幕在线| 精品亚洲乱码少妇综合久久| 久久女婷五月综合色啪小说| 欧美日韩一级在线毛片| 日韩大片免费观看网站| 亚洲国产最新在线播放| 99久久人妻综合| 91精品三级在线观看| 超色免费av| 成人影院久久| 午夜激情av网站| 精品一区二区三卡| 成年美女黄网站色视频大全免费| 一本色道久久久久久精品综合| 日日摸夜夜添夜夜爱| 黑人巨大精品欧美一区二区蜜桃| 精品国产一区二区三区久久久樱花| 少妇人妻 视频| 男人爽女人下面视频在线观看| 午夜福利视频在线观看免费| 满18在线观看网站| 人人澡人人妻人| 国产日韩欧美亚洲二区| 久久99一区二区三区| 各种免费的搞黄视频| 欧美国产精品va在线观看不卡| 久久精品aⅴ一区二区三区四区| 母亲3免费完整高清在线观看| svipshipincom国产片| 侵犯人妻中文字幕一二三四区| 国产精品香港三级国产av潘金莲 | 亚洲国产日韩一区二区| 欧美精品人与动牲交sv欧美| 国产男女内射视频| 亚洲精品在线美女| 午夜免费男女啪啪视频观看| 亚洲黑人精品在线| 久久久国产一区二区| 一边摸一边抽搐一进一出视频| 天天躁狠狠躁夜夜躁狠狠躁| 男女下面插进去视频免费观看| 国产成人免费观看mmmm| 丝袜美足系列| 日韩 欧美 亚洲 中文字幕| 香蕉丝袜av| 99国产精品一区二区蜜桃av | 叶爱在线成人免费视频播放| av网站在线播放免费| 水蜜桃什么品种好| 91精品三级在线观看| 中文字幕色久视频| 国产精品久久久久久精品古装| 人妻一区二区av| 久久久亚洲精品成人影院| 成人国产av品久久久| 国产免费又黄又爽又色| 男的添女的下面高潮视频| 国产精品 欧美亚洲| 久久国产精品影院| 精品一区在线观看国产| 国产野战对白在线观看| 九草在线视频观看| www.精华液| av在线app专区| a级毛片在线看网站| 天堂8中文在线网| 美女视频免费永久观看网站| 色网站视频免费| 日本午夜av视频| 国精品久久久久久国模美| 久久久久久人人人人人| 日韩人妻精品一区2区三区| 国产成人免费无遮挡视频| 老司机深夜福利视频在线观看 | 亚洲国产av影院在线观看| 久久精品亚洲熟妇少妇任你| 午夜福利,免费看| e午夜精品久久久久久久| 亚洲精品第二区| 老司机影院毛片| 精品第一国产精品| 日本五十路高清| 亚洲av国产av综合av卡| 欧美乱码精品一区二区三区| 波多野结衣av一区二区av| 只有这里有精品99| 欧美性长视频在线观看| 宅男免费午夜| 性少妇av在线| 性色av一级| 男女免费视频国产| 午夜免费鲁丝| 涩涩av久久男人的天堂| 久9热在线精品视频| 2021少妇久久久久久久久久久| 宅男免费午夜| 亚洲伊人久久精品综合| 侵犯人妻中文字幕一二三四区| 亚洲av日韩精品久久久久久密 | 丝袜美足系列| 国产主播在线观看一区二区 | 国产成人欧美| 久久人妻福利社区极品人妻图片 | 国产av一区二区精品久久| 成人黄色视频免费在线看| 美女福利国产在线| 亚洲人成网站在线观看播放| 菩萨蛮人人尽说江南好唐韦庄| 亚洲精品日本国产第一区| 婷婷色综合www| 美女国产高潮福利片在线看| 宅男免费午夜| 可以免费在线观看a视频的电影网站| 午夜视频精品福利| 交换朋友夫妻互换小说| 人人澡人人妻人| 乱人伦中国视频| 亚洲一码二码三码区别大吗| 国产1区2区3区精品| av欧美777| 一级,二级,三级黄色视频| av片东京热男人的天堂| 一级毛片女人18水好多 | 国产欧美日韩一区二区三 | 中文字幕精品免费在线观看视频| av线在线观看网站| 亚洲av日韩精品久久久久久密 | 日本色播在线视频| 两个人看的免费小视频| 精品少妇一区二区三区视频日本电影| 国产精品香港三级国产av潘金莲 | 亚洲欧美日韩高清在线视频 | 精品亚洲成a人片在线观看| 国产精品久久久人人做人人爽| 国产在线免费精品| 亚洲精品久久久久久婷婷小说| 爱豆传媒免费全集在线观看| 日日摸夜夜添夜夜爱| 色婷婷久久久亚洲欧美| 国产成人欧美| 欧美激情 高清一区二区三区| 亚洲人成电影免费在线| 欧美国产精品va在线观看不卡| 五月开心婷婷网| av又黄又爽大尺度在线免费看| 悠悠久久av| 男的添女的下面高潮视频| 国产1区2区3区精品| 亚洲久久久国产精品| 麻豆国产av国片精品| 亚洲精品日本国产第一区| www.av在线官网国产| 亚洲综合色网址| 狠狠精品人妻久久久久久综合| 欧美精品人与动牲交sv欧美| 亚洲中文日韩欧美视频| 热99久久久久精品小说推荐| 亚洲伊人久久精品综合| 国产视频一区二区在线看| 中文字幕人妻丝袜制服| 真人做人爱边吃奶动态| 少妇被粗大的猛进出69影院| 一本—道久久a久久精品蜜桃钙片| 丰满饥渴人妻一区二区三| 国产成人精品久久二区二区91| 女人爽到高潮嗷嗷叫在线视频| 日本黄色日本黄色录像| 欧美精品av麻豆av| 国产xxxxx性猛交| 人人妻人人澡人人看| 亚洲成人免费电影在线观看 | 校园人妻丝袜中文字幕| 日韩精品免费视频一区二区三区| 国产成人91sexporn| 国产高清视频在线播放一区 | 久久国产精品大桥未久av| 亚洲国产中文字幕在线视频| 国产在线一区二区三区精| 久久精品久久久久久噜噜老黄| av不卡在线播放| 久久亚洲国产成人精品v| 精品一区二区三区四区五区乱码 | 黄色 视频免费看| 国产精品久久久久久人妻精品电影 | 少妇猛男粗大的猛烈进出视频| 久久亚洲精品不卡| av又黄又爽大尺度在线免费看| 精品亚洲乱码少妇综合久久| 久9热在线精品视频| 秋霞在线观看毛片| 久久99一区二区三区| 色播在线永久视频| 亚洲男人天堂网一区| 欧美黄色淫秽网站| 建设人人有责人人尽责人人享有的| 久久中文字幕一级| 久久国产精品人妻蜜桃| 丝瓜视频免费看黄片| 久久精品成人免费网站| 我要看黄色一级片免费的| 亚洲精品美女久久久久99蜜臀 | 999久久久国产精品视频| 在线观看免费日韩欧美大片| 手机成人av网站| 精品国产乱码久久久久久男人| 国产免费视频播放在线视频| 亚洲第一青青草原| 少妇人妻 视频| 亚洲图色成人| 国产成人一区二区三区免费视频网站 | 王馨瑶露胸无遮挡在线观看| 国产亚洲欧美在线一区二区| 精品少妇久久久久久888优播| 久热这里只有精品99| 两性夫妻黄色片| 中文字幕高清在线视频| 一区福利在线观看| 亚洲人成电影免费在线| 美国免费a级毛片| 在线观看免费视频网站a站| 男女下面插进去视频免费观看| √禁漫天堂资源中文www| 亚洲熟女毛片儿| 成年人免费黄色播放视频| 国产色视频综合| 免费在线观看日本一区| 亚洲av成人不卡在线观看播放网 | 韩国高清视频一区二区三区| 黑丝袜美女国产一区| 久久久久精品国产欧美久久久 | 国产黄频视频在线观看| 精品少妇内射三级| 成年动漫av网址| 女警被强在线播放| 国产视频一区二区在线看| 麻豆av在线久日| 亚洲精品成人av观看孕妇| 久久99精品国语久久久| 亚洲五月色婷婷综合| 男女边摸边吃奶| 又紧又爽又黄一区二区| 中文字幕人妻丝袜制服| 一本久久精品| 黑丝袜美女国产一区| 午夜福利视频精品| 亚洲精品美女久久av网站| av天堂久久9| 18禁国产床啪视频网站| 久久热在线av| 在线天堂中文资源库| 脱女人内裤的视频| 在线天堂中文资源库| 成人亚洲欧美一区二区av| 男女国产视频网站| 国产一卡二卡三卡精品| av天堂久久9| a级片在线免费高清观看视频| 欧美少妇被猛烈插入视频| 日韩 欧美 亚洲 中文字幕| 日本猛色少妇xxxxx猛交久久| 精品国产一区二区三区四区第35| 色综合欧美亚洲国产小说| 国产野战对白在线观看| 国产97色在线日韩免费| 午夜影院在线不卡| 国产男人的电影天堂91| 青春草视频在线免费观看| www.精华液| 91麻豆精品激情在线观看国产 | 精品人妻在线不人妻| 制服人妻中文乱码| 深夜精品福利| 日日爽夜夜爽网站| 国产精品.久久久| 黄色一级大片看看| 中文字幕高清在线视频| 亚洲人成77777在线视频| 咕卡用的链子| 亚洲av欧美aⅴ国产|