Pub Date : 2000-04-01DOI: 10.1002/1521-3838(200004)19:2<149::AID-QSAR149>3.0.CO;2-9
A. Vedani, D. McMasters, M. Dobler
Quantitative structure-activity relationship (QSAR) is an area of computational research which builds mathematical or atomistic models to predict biological activities of molecules. While more powerful approaches make use of a genetic algorithm to reduce the bias with respect to model construction, the predictive power of the resulting surrogate still critically depends on the spatial alignment of the ligand molecules used to construct it. The 4D-QSAR concept Quasar developed at our laboratory not only takes local induced fit and H-bond flip-flop into account but also allows for the representation of the ligand molecules by an ensemble of conformations and/or orientations. The contribution of a single entity within this ensemble to the total ligand-receptor interaction energy is determined by a Boltzmann criterion. The three-dimensional surrogate is represented by a family of receptor-surface models, populated with atomistic properties—hydrogen bonds, salt bridges, hydrophobic particles, and solvent—mapped onto it. Quasar has been used to establish QSARs for the enzyme dopamine β-hydroxylase and for the aryl hydrocarbon receptor. The surrogates were able to predict free energies of ligand binding, ΔG°, for external sets of 15 and 26 test ligand molecules, respectively, to within 0.7 kcal/mol (rms) of the experimental value, with the largest individual deviation not exceeding 1.3 kcal/mol. The results indicate that the use of a multiple-ligand representation is superior to a single-conformer concept and reduces the user bias associated with the ligand alignment. Moreover, the selection protocol demonstrates that the technique is capable of identifying a small number of active conformations and does not prefer a larger selection of lesser-contributing entities.
{"title":"Multi-conformational Ligand Representation in 4D-QSAR: Reducing the Bias Associated with Ligand Alignment","authors":"A. Vedani, D. McMasters, M. Dobler","doi":"10.1002/1521-3838(200004)19:2<149::AID-QSAR149>3.0.CO;2-9","DOIUrl":"https://doi.org/10.1002/1521-3838(200004)19:2<149::AID-QSAR149>3.0.CO;2-9","url":null,"abstract":"Quantitative structure-activity relationship (QSAR) is an area of computational research which builds mathematical or atomistic models to predict biological activities of molecules. While more powerful approaches make use of a genetic algorithm to reduce the bias with respect to model construction, the predictive power of the resulting surrogate still critically depends on the spatial alignment of the ligand molecules used to construct it. The 4D-QSAR concept Quasar developed at our laboratory not only takes local induced fit and H-bond flip-flop into account but also allows for the representation of the ligand molecules by an ensemble of conformations and/or orientations. The contribution of a single entity within this ensemble to the total ligand-receptor interaction energy is determined by a Boltzmann criterion. The three-dimensional surrogate is represented by a family of receptor-surface models, populated with atomistic properties—hydrogen bonds, salt bridges, hydrophobic particles, and solvent—mapped onto it. \u0000 \u0000 \u0000 \u0000Quasar has been used to establish QSARs for the enzyme dopamine β-hydroxylase and for the aryl hydrocarbon receptor. The surrogates were able to predict free energies of ligand binding, ΔG°, for external sets of 15 and 26 test ligand molecules, respectively, to within 0.7 kcal/mol (rms) of the experimental value, with the largest individual deviation not exceeding 1.3 kcal/mol. The results indicate that the use of a multiple-ligand representation is superior to a single-conformer concept and reduces the user bias associated with the ligand alignment. Moreover, the selection protocol demonstrates that the technique is capable of identifying a small number of active conformations and does not prefer a larger selection of lesser-contributing entities.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"120 1","pages":"149-161"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80760725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-04-01DOI: 10.1002/1521-3838(200004)19:2<173::AID-QSAR173>3.0.CO;2-L
Roberta de Faria Rodrigues, J. C. Lopes, C. Montanari
{"title":"A QSAR Study on Pneumocystis carinii Topoisomerases of bis‐Benzimidazoles","authors":"Roberta de Faria Rodrigues, J. C. Lopes, C. Montanari","doi":"10.1002/1521-3838(200004)19:2<173::AID-QSAR173>3.0.CO;2-L","DOIUrl":"https://doi.org/10.1002/1521-3838(200004)19:2<173::AID-QSAR173>3.0.CO;2-L","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"1 1","pages":"173-175"},"PeriodicalIF":0.0,"publicationDate":"2000-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89449336","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<29::AID-QSAR29>3.0.CO;2-P
G. Bravi, J. Wikel
{"title":"Application of MS‐WHIM Descriptors: 1. Introduction of New Molecular Surface Properties and 2. Prediction of Binding Affinity Data","authors":"G. Bravi, J. Wikel","doi":"10.1002/(SICI)1521-3838(200002)19:1<29::AID-QSAR29>3.0.CO;2-P","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<29::AID-QSAR29>3.0.CO;2-P","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"4 1","pages":"29-38"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74379846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<39::AID-QSAR39>3.0.CO;2-N
G. Bravi, J. Wikel
MS-WHIM descriptors were developed in attempt to capture global 3D chemical information at molecular surface level. Initially, they contained information about size, shape and electrostatic distribution of a molecule. More recently they were enriched introducing new molecular surface properties related to hydrogen bonding capacity and hydrophobicity. This paper reports the application of expanded MS-WHIM descriptors to model: i) logP of 268 small organic molecules, ii) Caco-2 cell permeability of 17 heterogeneous compounds, and iii) pKa values of 15 substituted imidazoles. PLS regressions were derived and validated through cross-validation, repeated scrambling of the response variables, and test set predictions. The analysis of PLS models showed that MS-WHIM provided meaningful structure-property correlations: i) q2=0.709, ii) q2=0.797, and iii) q2=0.728. Hydrogen bonding capacity and hydrophobicity played a significant role and considerably improved the results. MS-WHIM descriptors, due to their holistic character, appear to be usefully applicable to a wide variety of chemical and biological problems.
{"title":"Application of MS-WHIM Descriptors: 3. Prediction of Molecular Properties","authors":"G. Bravi, J. Wikel","doi":"10.1002/(SICI)1521-3838(200002)19:1<39::AID-QSAR39>3.0.CO;2-N","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<39::AID-QSAR39>3.0.CO;2-N","url":null,"abstract":"MS-WHIM descriptors were developed in attempt to capture global 3D chemical information at molecular surface level. Initially, they contained information about size, shape and electrostatic distribution of a molecule. More recently they were enriched introducing new molecular surface properties related to hydrogen bonding capacity and hydrophobicity. This paper reports the application of expanded MS-WHIM descriptors to model: i) logP of 268 small organic molecules, ii) Caco-2 cell permeability of 17 heterogeneous compounds, and iii) pKa values of 15 substituted imidazoles. PLS regressions were derived and validated through cross-validation, repeated scrambling of the response variables, and test set predictions. The analysis of PLS models showed that MS-WHIM provided meaningful structure-property correlations: i) q2=0.709, ii) q2=0.797, and iii) q2=0.728. Hydrogen bonding capacity and hydrophobicity played a significant role and considerably improved the results. MS-WHIM descriptors, due to their holistic character, appear to be usefully applicable to a wide variety of chemical and biological problems.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"18 1","pages":"39-49"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84708851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<22::AID-QSAR22>3.0.CO;2-U
P. S. Magee
{"title":"Exploring the Chemistry of Quinones by Computation","authors":"P. S. Magee","doi":"10.1002/(SICI)1521-3838(200002)19:1<22::AID-QSAR22>3.0.CO;2-U","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<22::AID-QSAR22>3.0.CO;2-U","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"129 1","pages":"22-28"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82858333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<10::AID-QSAR10>3.0.CO;2-7
H. Chuman, S. Goto, M. Karasawa, M. Sasaki, U. Nagashima, K. Nishimura, T. Fujita
The three-dimensional “bioactive” conformations of various types of pyrethroid insecticides were deduced from among optimized conformations which were generated on the basis of the exhaustive conformational exploration of the reference compound, MTI-800. A “folded” rather than an “extended” conformation was proposed to be the “bioactive structure” of pyrethroid molecules included in this study. The folded “bioactive” structures were further analyzed in terms of molecular (dis)similarity indices to elucidate the effect of the “local” structural variations on the activity. The results indicate that the overall bioactive conformation as well as the local 3D similarity of the molecule are important in governing the potency variations in the insecticidal activity.
{"title":"Three-Dimensional Structure-Activity Relationships of Synthetic Pyrethroids: 1. Similarity in Bioactive Conformations and Their Structure-Activity Pattern","authors":"H. Chuman, S. Goto, M. Karasawa, M. Sasaki, U. Nagashima, K. Nishimura, T. Fujita","doi":"10.1002/(SICI)1521-3838(200002)19:1<10::AID-QSAR10>3.0.CO;2-7","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<10::AID-QSAR10>3.0.CO;2-7","url":null,"abstract":"The three-dimensional “bioactive” conformations of various types of pyrethroid insecticides were deduced from among optimized conformations which were generated on the basis of the exhaustive conformational exploration of the reference compound, MTI-800. A “folded” rather than an “extended” conformation was proposed to be the “bioactive structure” of pyrethroid molecules included in this study. The folded “bioactive” structures were further analyzed in terms of molecular (dis)similarity indices to elucidate the effect of the “local” structural variations on the activity. The results indicate that the overall bioactive conformation as well as the local 3D similarity of the molecule are important in governing the potency variations in the insecticidal activity.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"3 1","pages":"10-21"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78857011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<3::AID-QSAR3>3.0.CO;2-N
J. Dearden, M. Cronin, Yuanhui Zhao, O. Raevsky
The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.
{"title":"QSAR Studies of Compounds Acting by Polar and Non-polar Narcosis: an Examination of the Role of Polarisability and Hydrogen Bonding","authors":"J. Dearden, M. Cronin, Yuanhui Zhao, O. Raevsky","doi":"10.1002/(SICI)1521-3838(200002)19:1<3::AID-QSAR3>3.0.CO;2-N","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<3::AID-QSAR3>3.0.CO;2-N","url":null,"abstract":"The toxicities of 33 non-polar narcotics and 15 polar narcotics have been correlated with the logarithm of the octanol-water partition coefficient (log P). Correlations have also been obtained of toxicities with polarisabilities (α) and free energy hydrogen bond acceptor factors (Ca) calculated using HYBOT-PLUS. There are clear differences in the way non-polar and polar narcotics correlate with log P and with α and Ca, indicating that the two classes of compound exert their toxicity by somewhat different mechanisms.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"20 1","pages":"3-9"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91049591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2000-02-01DOI: 10.1002/(SICI)1521-3838(200002)19:1<50::AID-QSAR50>3.0.CO;2-#
Hong-yu Zhang
The difference of heat of formation between parent molecule and its free radical (ΔHOF), calculated by semiempirical quantum chemical method AM1, was employed as a theoretical index to characterize the O–H bond dissociation energy (BDE) of antioxidant. Through a comparison between ΔHOF of model molecules, it was found that 6,7-dihydroxyflavone (DHF) possessed two favorable structural factors, the presence of ortho hydroxyls and the existence of para oxygen, to weaken its O–H bond at position 6, but the passive effect produced by electron-withdrawing property of the chromonoid ring C surpassed the active effect of the para oxygen. Therefore the free radical scavenging activity of DHF was lower than that of quercetin which possessed catecholic hydroxyl in ring B and was scarcely influenced by ring C. As a result of the analysis, two more active flavonoid antioxidants were constructed theoretically.
{"title":"Theoretical Investigation on Free Radical Scavenging Activity of 6,7‐Dihydroxyflavone","authors":"Hong-yu Zhang","doi":"10.1002/(SICI)1521-3838(200002)19:1<50::AID-QSAR50>3.0.CO;2-#","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(200002)19:1<50::AID-QSAR50>3.0.CO;2-#","url":null,"abstract":"The difference of heat of formation between parent molecule and its free radical (ΔHOF), calculated by semiempirical quantum chemical method AM1, was employed as a theoretical index to characterize the O–H bond dissociation energy (BDE) of antioxidant. Through a comparison between ΔHOF of model molecules, it was found that 6,7-dihydroxyflavone (DHF) possessed two favorable structural factors, the presence of ortho hydroxyls and the existence of para oxygen, to weaken its O–H bond at position 6, but the passive effect produced by electron-withdrawing property of the chromonoid ring C surpassed the active effect of the para oxygen. Therefore the free radical scavenging activity of DHF was lower than that of quercetin which possessed catecholic hydroxyl in ring B and was scarcely influenced by ring C. As a result of the analysis, two more active flavonoid antioxidants were constructed theoretically.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"30 1","pages":"50-53"},"PeriodicalIF":0.0,"publicationDate":"2000-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74221163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1999-12-01DOI: 10.1002/(SICI)1521-3838(199912)18:6<584::AID-QSAR584>3.0.CO;2-B
Gyula Oros, T. Cserháti
The growth inhibitory effect of 38 thiophosphorylglycinamide (TPGA) derivatives against 25 fungal species (test organisms) belonging to various taxonomic groups was determined. Principal component analysis (PCA) was used for the elucidation of similarities and dissimilarities between TPGAs and between fungi. The strength (potency) and selectivity of the fungicidal effect were separated by the spectral mapping technique (SPM). The dimensionality of the matrices of PC loadings and variables and the selectivity maps were reduced to two by the nonlinear mapping technique. PCA and SPM were compared by calculating linear relationships between the potency values and the corresponding coordinates of maps calculated by PCA and SPM. The relationship between fungicidal effect and molecular structure was elucidated by stepwise regression analysis. It was established that the coordinates of maps are orthogonal and the results of PCA and SPM are similar but not identical. The advantage of SPM is the separation of the strength and selectivity of fungicidal effect facilitating the rational design of new TPGA derivatives. Stepwise regression analysis indicated that the position of substituents in the TPGA molecule, its bulkiness and hydrophobicity exert the highest impact on both the strength and selectivity of fungicidal effect. No relationship was found between sensitivity of fungal species towards TPGAs and their taxonomic position.
{"title":"QSAR Study of the Fungicidal Activity of Thiophosphorylglycinamide Derivatives. Comparison of Principal Component Analysis and Spectral Mapping Technique","authors":"Gyula Oros, T. Cserháti","doi":"10.1002/(SICI)1521-3838(199912)18:6<584::AID-QSAR584>3.0.CO;2-B","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199912)18:6<584::AID-QSAR584>3.0.CO;2-B","url":null,"abstract":"The growth inhibitory effect of 38 thiophosphorylglycinamide (TPGA) derivatives against 25 fungal species (test organisms) belonging to various taxonomic groups was determined. Principal component analysis (PCA) was used for the elucidation of similarities and dissimilarities between TPGAs and between fungi. The strength (potency) and selectivity of the fungicidal effect were separated by the spectral mapping technique (SPM). The dimensionality of the matrices of PC loadings and variables and the selectivity maps were reduced to two by the nonlinear mapping technique. PCA and SPM were compared by calculating linear relationships between the potency values and the corresponding coordinates of maps calculated by PCA and SPM. The relationship between fungicidal effect and molecular structure was elucidated by stepwise regression analysis. It was established that the coordinates of maps are orthogonal and the results of PCA and SPM are similar but not identical. The advantage of SPM is the separation of the strength and selectivity of fungicidal effect facilitating the rational design of new TPGA derivatives. Stepwise regression analysis indicated that the position of substituents in the TPGA molecule, its bulkiness and hydrophobicity exert the highest impact on both the strength and selectivity of fungicidal effect. No relationship was found between sensitivity of fungal species towards TPGAs and their taxonomic position.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"70 1","pages":"584-593"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73193965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 1999-12-01DOI: 10.1002/(SICI)1521-3838(199912)18:6<573::AID-QSAR573>3.0.CO;2-J
M. Drew, J. Lumley, N. Price
{"title":"Predicting Ecotoxicology of Organophosphorous Insecticides: Successful Parameter Selection with the Genetic Function Algorithm","authors":"M. Drew, J. Lumley, N. Price","doi":"10.1002/(SICI)1521-3838(199912)18:6<573::AID-QSAR573>3.0.CO;2-J","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199912)18:6<573::AID-QSAR573>3.0.CO;2-J","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"17 1","pages":"573-583"},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75322534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：