芳香羧酸衍生物驱避剂的非线性定量构效关系
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摘要
【目的】驱避剂可使害虫不敢接近受用者从而保护受用者免遭其害。建立高精度、可解释性强的非线性定量构效关系(quantitative structure-activity relationship,QSAR)模型对设计合成新的高效昆虫驱避剂有重要意义。【方法】基于37个芳香羧酸类化合物对家蝇Musca domestica的驱避活性,以量子化学计算软件PCLIENT获取每一化合物初始描述符,以二元矩阵重排过滤器、多轮末尾淘汰实施特征非线性筛选,以支持向量回归(support vector regression,SVR)建立非线性QSAR模型,以SVR非线性解释体系分析各保留描述符对驱避活性的影响。【结果】1 542个初始描述符的SVR模型F=1.2,特征筛选后6个保留描述符的SVR模型F=184.6,特征筛选对QSAR模型精度有重要影响。6个保留分子描述符的重要性依次为p4BCD>GATS7v>T(O..O)>JGI8>SssO>nArCONR2。【结论】保留描述符与芳香羧酸类化合物对家蝇驱避活性的非线性关系明显,获得了高精度、普适性强的非线性SVR-QSAR模型。
【Aim】Repellent can protect the users by driving target pests away from them. It is important to establish a nonlinear quantitative structure-activity relationship( QSAR) model with high precision and strong interpretation for designing and synthesizing the new insect repellent with higher bioactivity.【Methods】Based on the repellent activities of 37 aromatic carboxylic acid derivatives against the housefly,Musca domestica,the initial descriptors were generated with stoichiometry software PCLIENT,and then the binary matrix shuffling filter( BMSF) and worst descriptor elimination multi-round method( WDEM) were successively used to conduct the nonlinear selection for initial descriptors. With the reserved descriptors,a support vector regression( SVR) model was established for the QSAR analysis of these 37 repellent derivatives. The influence of reserved descriptors on repellent activities was further analyzed with SVR interpretation system. 【Results】The F-score of SVR model with original 1 542 descriptors was 1. 2. However,it was 184. 6 with the retained six descriptors after feature screening,indicating that feature screening has important effects on the precision of QSAR model. The importance of six molecular descriptors was as follows: p4 BCD > GATS7 v > T( O.. O) > JGI8 > SssO > nArCONR2.【Conclusion】The nonlinear relationship between reserved descriptors and the repellent activities of aromatic carboxylic acid derivatives against M. domestica was remarkable,and a high-performance SVRQSAR model for repellent derivatives was constructed.
【Aim】Repellent can protect the users by driving target pests away from them. It is important to establish a nonlinear quantitative structure-activity relationship( QSAR) model with high precision and strong interpretation for designing and synthesizing the new insect repellent with higher bioactivity.【Methods】Based on the repellent activities of 37 aromatic carboxylic acid derivatives against the housefly,Musca domestica,the initial descriptors were generated with stoichiometry software PCLIENT,and then the binary matrix shuffling filter( BMSF) and worst descriptor elimination multi-round method( WDEM) were successively used to conduct the nonlinear selection for initial descriptors. With the reserved descriptors,a support vector regression( SVR) model was established for the QSAR analysis of these 37 repellent derivatives. The influence of reserved descriptors on repellent activities was further analyzed with SVR interpretation system. 【Results】The F-score of SVR model with original 1 542 descriptors was 1. 2. However,it was 184. 6 with the retained six descriptors after feature screening,indicating that feature screening has important effects on the precision of QSAR model. The importance of six molecular descriptors was as follows: p4 BCD > GATS7 v > T( O.. O) > JGI8 > SssO > nArCONR2.【Conclusion】The nonlinear relationship between reserved descriptors and the repellent activities of aromatic carboxylic acid derivatives against M. domestica was remarkable,and a high-performance SVRQSAR model for repellent derivatives was constructed.
引文
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Chang CC,Lin CJ,2011.LIBSVM:a library for support vectormachines.ACM Transactions on Intelligent Systems and Technology,2(3):27.
Dai CG,Li KL,Wang LF,Tan XS,Hu Y,Yuan ZM,Fu Q,2013.Anoligidic diet for Sesamia inferens optimized by uniform design andsuccessive rearing.Chin.J.Rice Sci.,27(4):434-439.[戴长庚,李凯龙,王立峰,谭显胜,胡阳,袁哲明,傅强,2013.基于均匀设计优化的大螟实用饲料配方及继代饲养.中国水稻科学,27(4):434-439]
Dai ZJ,Zhou W,Yuan ZM,2011.A novel method of nonlinear rapidfeature selection for high dimensional data and its application inpeptide QSAR modeling based on support vector machine.ActaPhys.Chim.Sin.,27(7):1654-1660.[代志军,周玮,袁哲明,2011.基于支持向量机的高维特征非线性快速筛选与肽QSAR建模.物理化学学报,27(7):1654-1660]
Ditzen M,Pellegrino M,Vosshall LB,2008.Insect odorant receptors aremolecular targets of the insect repellent DEET.Science,319(5871):1838-1842.
Garcoa-Domenech R,Aguilera J,Moncef AE,Pocovi S,Gálvez J,2010.Application of molecular topology to the prediction ofmosquito repellents of a group of terpenoid compounds.MolecularDiversity,14(2):321-329.
Hao HL,Deng XJ,Du JW,2006.Extraction of catnip essential oilcomponents and their repellent activity against Aedes albopictus andCulex pipiens pallens.Acta Entomologica Sinica,49(3):533-537.[郝蕙玲,邓晓军,杜家纬,2006.猫薄荷精油有效成分的提取及其对白纹伊蚊、淡色库蚊的驱避活性.昆虫学报,49(3):533-537]
Katritzky AR,Dobchev DA,Tulp I,Karelsonc M,Carlson DA,2006.QSAR study of mosquito repellents using Codessa Pro.Bioorg.Med.Chem.Lett.,16(8):2306-2311.
Katritzky AR,Wang ZQ,Slavov S,Tsikolia M,Dobchev D,AkhmedovNG,Hall CD,Bernier UR,Clark CC,Linthicum KJ,2008.Synthesis and bioassay of improved mosquito repellents predictedfrom chemical structure.Proc.Natl.Acad.Sci.USA,105(21):7359-7364.
Li J,Tan XS,Tan SQ,Yuan ZM,Xiong XY,2010.Application ofimproved support vector machine in the optimization of artificial dietfor the cotton bollworm,Helicoverpa armigera(Lepidoptera:Noctuidae).Acta Entomologica Sinica,53(4):420-426.[李俊,谭显胜,谭泗桥,袁哲明,熊兴耀,2010.改进支持向量机在棉铃虫人工饲料配方优化中的应用.昆虫学报,53(4):420-426]
Liao SL,Jiang ZK,Song J,Wang ZD,Han ZJ,Chen JZ,2012a.Repelling mechanism of mosquitoes repellent.Chinese Journal ofHygienic Insecticides&Equipments,18(4):280-283.[廖圣良,姜志宽,宋杰,王宗德,韩招久,陈金珠,2012a.蚊虫驱避剂的驱避机理研究.中华卫生杀虫药械,18(4):280-283]
Liao SL,Song J,Wang ZD,Chen JZ,Chen SX,Fan GR,Jiang ZK,Han ZJ,2012b.Quantitative calculation of the influence of themolecular association between terpenoid repellents and CO2on theirrepellency against mosquitoes.Acta Entomologica Sinica,55(9):1054-1061.[廖圣良,宋杰,王宗德,陈金珠,陈尚钘,范国荣,姜志宽,韩招久,2012b.定量计算萜类驱避化合物与二氧化碳缔合对其蚊虫驱避活性的影响.昆虫学报,55(9):1054-1061]
Natarajan R,Basak SC,Mills D,Kraker JJ,Hawkins DM,2008.Quantitative structure-activity relationship modeling of mosquitorepellents using calculated descriptors.Croatica Chemica Acta,81(2):333-340.
Oliferenko PV,Oliferenko AA,Poda GI,Osolodkin DI,Pillai GG,Bernier UR,Tsikolia M,Agramonte NM,Clark GG,Linthicum KJ,Katritzky AR,2013.Promising Aedes aegypti repellent chemotypesidentified through integrated QSAR,virtual screening,synthesis,and bioassay.PLoS ONE,8(9):e64547.
Sato K,Pellegrino M,Nakagawa T,Nakagawa T,Vosshall LB,TouharaK,2008.Insect olfactory receptors are heteromeric ligand-gated ionchannels.Nature,452(7190):1002-1006.
Suryanarayana MVS,Pandey KS,Prakash S,Raghuveeran CD,DangiRS,Swamy RV,Rao KM,1991.Structure-activity relationshipstudies with mosquito repellent amides.Journal of PharmaceuticalSciences,80(11):1055-1057.
Tan XS,Wang ZM,Tan SQ,Yuan ZM,Xiong XY,2009.Establishinginterpretability for support vector regression.Journal of SystemSimulation,21(24):7795-7797.[谭显胜,王志明,谭泗桥,袁哲明,熊兴耀,2009.支持向量回归可解释性体系的建立.系统仿真学报,21(24):7795-7797]
Vapnik VN,1995.The Nature of Statistical Learning Theory.SpringerVerlag Press,New York.87-189.
Wang ZD,Song J,Chen JZ,Song ZQ,Shang SB,Jiang ZK,Han ZJ,2008.QSAR study of mosquito repellents from terpenoid with a sixmember-ring.Bioorganic&Medicinal Chemistry Letters,18(9):2854-2859.
Wang ZD,Song J,Jiang ZK,Han ZJ,Chen JZ,Song ZQ,Shang SB,Chen C,2008.Study of the structure-activity relationship andmechanism of repellent.Chinese Journal of Hygienic Insecticides&Equipments,14(6):472-476.[王宗德,宋杰,姜志宽,韩招久,陈金珠,宋湛谦,商士斌,陈超,2008.驱避剂的构效关系和驱避机理的研究.中华卫生杀虫药械,14(6):472-476]
Wicher D,Schafer R,Bauernfeind R,Stensmyr MC,Heller R,Heinemann SH,Hansson BS,2008.Drosophila odorant receptorsare both ligand-gated and cyclic-nucleotide-activated cationchannels.Nature,452(7190):1007-1011.
Xue FQ,Wang HQ,Zhao RC,1997.Determination of repellency ofaromatic carboxylic acid derivatives to housefly in relationship toquantitative structure activity.Scientia Agricultura Sinica,30(1):77-83.[薛飞群,汪汉卿,赵荣材,1997.芳香羧酸衍生物驱避剂活性测定及定量构效关系的研究.中国农业科学,30(1):77-83]
Xue FQ,Wang YC,Xu ZZ,1999.Quantitative structure activityrelationship study with the aromatic acid repellents by molecularconnectivity.Chinese Journal of Veterinary Drug,33(2):12-15.[薛飞群,王玉春,徐忠赞,1999.分子连接性法分析芳香羧酸类驱避剂的构效关系.中国兽药杂志,33(2):12-15]
Zhang HY,Wang HY,Dai ZJ,Chen MS,Yuan ZM,2012.Improvingaccuracy for cancer classification with a new algorithm for genesselection.BMC Bioinformatics,13(1):298.
Zhong GH,Hu MY,2001.QSAR and its application and advance inpesticide design.Chinese Journal of Pesticide Science,3(2):1-11.[钟国华,胡美英,2001.QSAR及其在农药设计中的应用和进展.农药学学报,3(2):1-11]
Zhou SH,Li J,Yao RX,Zhang X,Yuan ZM,2012.Optimization ofchemically defined diet for larvae of the cotton bollworm(Helicoverpaarmigera)based on uniform design and support vector regression.Acta Entomologica Sinica,55(1):124-132.[周世豪,李俊,姚润贤,张星,袁哲明,2012.基于均匀设计与支持向量回归的棉铃虫幼虫全纯人工饲料配方优化.昆虫学报,55(1):124-132]
Chang CC,Lin CJ,2011.LIBSVM:a library for support vectormachines.ACM Transactions on Intelligent Systems and Technology,2(3):27.
Dai CG,Li KL,Wang LF,Tan XS,Hu Y,Yuan ZM,Fu Q,2013.Anoligidic diet for Sesamia inferens optimized by uniform design andsuccessive rearing.Chin.J.Rice Sci.,27(4):434-439.[戴长庚,李凯龙,王立峰,谭显胜,胡阳,袁哲明,傅强,2013.基于均匀设计优化的大螟实用饲料配方及继代饲养.中国水稻科学,27(4):434-439]
Dai ZJ,Zhou W,Yuan ZM,2011.A novel method of nonlinear rapidfeature selection for high dimensional data and its application inpeptide QSAR modeling based on support vector machine.ActaPhys.Chim.Sin.,27(7):1654-1660.[代志军,周玮,袁哲明,2011.基于支持向量机的高维特征非线性快速筛选与肽QSAR建模.物理化学学报,27(7):1654-1660]
Ditzen M,Pellegrino M,Vosshall LB,2008.Insect odorant receptors aremolecular targets of the insect repellent DEET.Science,319(5871):1838-1842.
Garcoa-Domenech R,Aguilera J,Moncef AE,Pocovi S,Gálvez J,2010.Application of molecular topology to the prediction ofmosquito repellents of a group of terpenoid compounds.MolecularDiversity,14(2):321-329.
Hao HL,Deng XJ,Du JW,2006.Extraction of catnip essential oilcomponents and their repellent activity against Aedes albopictus andCulex pipiens pallens.Acta Entomologica Sinica,49(3):533-537.[郝蕙玲,邓晓军,杜家纬,2006.猫薄荷精油有效成分的提取及其对白纹伊蚊、淡色库蚊的驱避活性.昆虫学报,49(3):533-537]
Katritzky AR,Dobchev DA,Tulp I,Karelsonc M,Carlson DA,2006.QSAR study of mosquito repellents using Codessa Pro.Bioorg.Med.Chem.Lett.,16(8):2306-2311.
Katritzky AR,Wang ZQ,Slavov S,Tsikolia M,Dobchev D,AkhmedovNG,Hall CD,Bernier UR,Clark CC,Linthicum KJ,2008.Synthesis and bioassay of improved mosquito repellents predictedfrom chemical structure.Proc.Natl.Acad.Sci.USA,105(21):7359-7364.
Li J,Tan XS,Tan SQ,Yuan ZM,Xiong XY,2010.Application ofimproved support vector machine in the optimization of artificial dietfor the cotton bollworm,Helicoverpa armigera(Lepidoptera:Noctuidae).Acta Entomologica Sinica,53(4):420-426.[李俊,谭显胜,谭泗桥,袁哲明,熊兴耀,2010.改进支持向量机在棉铃虫人工饲料配方优化中的应用.昆虫学报,53(4):420-426]
Liao SL,Jiang ZK,Song J,Wang ZD,Han ZJ,Chen JZ,2012a.Repelling mechanism of mosquitoes repellent.Chinese Journal ofHygienic Insecticides&Equipments,18(4):280-283.[廖圣良,姜志宽,宋杰,王宗德,韩招久,陈金珠,2012a.蚊虫驱避剂的驱避机理研究.中华卫生杀虫药械,18(4):280-283]
Liao SL,Song J,Wang ZD,Chen JZ,Chen SX,Fan GR,Jiang ZK,Han ZJ,2012b.Quantitative calculation of the influence of themolecular association between terpenoid repellents and CO2on theirrepellency against mosquitoes.Acta Entomologica Sinica,55(9):1054-1061.[廖圣良,宋杰,王宗德,陈金珠,陈尚钘,范国荣,姜志宽,韩招久,2012b.定量计算萜类驱避化合物与二氧化碳缔合对其蚊虫驱避活性的影响.昆虫学报,55(9):1054-1061]
Natarajan R,Basak SC,Mills D,Kraker JJ,Hawkins DM,2008.Quantitative structure-activity relationship modeling of mosquitorepellents using calculated descriptors.Croatica Chemica Acta,81(2):333-340.
Oliferenko PV,Oliferenko AA,Poda GI,Osolodkin DI,Pillai GG,Bernier UR,Tsikolia M,Agramonte NM,Clark GG,Linthicum KJ,Katritzky AR,2013.Promising Aedes aegypti repellent chemotypesidentified through integrated QSAR,virtual screening,synthesis,and bioassay.PLoS ONE,8(9):e64547.
Sato K,Pellegrino M,Nakagawa T,Nakagawa T,Vosshall LB,TouharaK,2008.Insect olfactory receptors are heteromeric ligand-gated ionchannels.Nature,452(7190):1002-1006.
Suryanarayana MVS,Pandey KS,Prakash S,Raghuveeran CD,DangiRS,Swamy RV,Rao KM,1991.Structure-activity relationshipstudies with mosquito repellent amides.Journal of PharmaceuticalSciences,80(11):1055-1057.
Tan XS,Wang ZM,Tan SQ,Yuan ZM,Xiong XY,2009.Establishinginterpretability for support vector regression.Journal of SystemSimulation,21(24):7795-7797.[谭显胜,王志明,谭泗桥,袁哲明,熊兴耀,2009.支持向量回归可解释性体系的建立.系统仿真学报,21(24):7795-7797]
Vapnik VN,1995.The Nature of Statistical Learning Theory.SpringerVerlag Press,New York.87-189.
Wang ZD,Song J,Chen JZ,Song ZQ,Shang SB,Jiang ZK,Han ZJ,2008.QSAR study of mosquito repellents from terpenoid with a sixmember-ring.Bioorganic&Medicinal Chemistry Letters,18(9):2854-2859.
Wang ZD,Song J,Jiang ZK,Han ZJ,Chen JZ,Song ZQ,Shang SB,Chen C,2008.Study of the structure-activity relationship andmechanism of repellent.Chinese Journal of Hygienic Insecticides&Equipments,14(6):472-476.[王宗德,宋杰,姜志宽,韩招久,陈金珠,宋湛谦,商士斌,陈超,2008.驱避剂的构效关系和驱避机理的研究.中华卫生杀虫药械,14(6):472-476]
Wicher D,Schafer R,Bauernfeind R,Stensmyr MC,Heller R,Heinemann SH,Hansson BS,2008.Drosophila odorant receptorsare both ligand-gated and cyclic-nucleotide-activated cationchannels.Nature,452(7190):1007-1011.
Xue FQ,Wang HQ,Zhao RC,1997.Determination of repellency ofaromatic carboxylic acid derivatives to housefly in relationship toquantitative structure activity.Scientia Agricultura Sinica,30(1):77-83.[薛飞群,汪汉卿,赵荣材,1997.芳香羧酸衍生物驱避剂活性测定及定量构效关系的研究.中国农业科学,30(1):77-83]
Xue FQ,Wang YC,Xu ZZ,1999.Quantitative structure activityrelationship study with the aromatic acid repellents by molecularconnectivity.Chinese Journal of Veterinary Drug,33(2):12-15.[薛飞群,王玉春,徐忠赞,1999.分子连接性法分析芳香羧酸类驱避剂的构效关系.中国兽药杂志,33(2):12-15]
Zhang HY,Wang HY,Dai ZJ,Chen MS,Yuan ZM,2012.Improvingaccuracy for cancer classification with a new algorithm for genesselection.BMC Bioinformatics,13(1):298.
Zhong GH,Hu MY,2001.QSAR and its application and advance inpesticide design.Chinese Journal of Pesticide Science,3(2):1-11.[钟国华,胡美英,2001.QSAR及其在农药设计中的应用和进展.农药学学报,3(2):1-11]
Zhou SH,Li J,Yao RX,Zhang X,Yuan ZM,2012.Optimization ofchemically defined diet for larvae of the cotton bollworm(Helicoverpaarmigera)based on uniform design and support vector regression.Acta Entomologica Sinica,55(1):124-132.[周世豪,李俊,姚润贤,张星,袁哲明,2012.基于均匀设计与支持向量回归的棉铃虫幼虫全纯人工饲料配方优化.昆虫学报,55(1):124-132]