Pub Date : 2002-05-01DOI: 10.1002/1521-3838(200205)21:1<3::aid-qsar3>3.0.co;2-d
M. Bohác, Björn Loeprecht, J. Damborský, G. Schüürmann
The impact of orthogonal signal correction (OSC) on the prediction power of CoMFA models was studied using a data set of 47 nitrobenzenes with toxicities (log 1/IC50) towards the aquatic ciliates Tetrahymena pyriformis. Comparative analyses of different data pre-treatments shows that block unscaled weighting (BUW) results in significantly better PLS models than no scaling, centering or autoscaling for OSC. One OSC component is optimal for the signal correction and reduces the X variance by about 40%. While OSC yields improved calibration and cross-validation statistics, standard CoMFA is superior with respect to the external prediction power as evaluated by models built from complementary subsets. Moreover, external prediction reveals some cases of severe OSC overfitting, which needs attention in future investigations.
{"title":"Impact of Orthogonal Signal Correction (OSC) on the Predictive Ability of CoMFA Models for the Ciliate Toxicity of Nitrobenzenes Dedicated to Professor Werner Klein, Schmallenberg (Germany), on the oaccastion of his 65th birthday","authors":"M. Bohác, Björn Loeprecht, J. Damborský, G. Schüürmann","doi":"10.1002/1521-3838(200205)21:1<3::aid-qsar3>3.0.co;2-d","DOIUrl":"https://doi.org/10.1002/1521-3838(200205)21:1<3::aid-qsar3>3.0.co;2-d","url":null,"abstract":"The impact of orthogonal signal correction (OSC) on the prediction power of CoMFA models was studied using a data set of 47 nitrobenzenes with toxicities (log 1/IC50) towards the aquatic ciliates Tetrahymena pyriformis. Comparative analyses of different data pre-treatments shows that block unscaled weighting (BUW) results in significantly better PLS models than no scaling, centering or autoscaling for OSC. One OSC component is optimal for the signal correction and reduces the X variance by about 40%. While OSC yields improved calibration and cross-validation statistics, standard CoMFA is superior with respect to the external prediction power as evaluated by models built from complementary subsets. Moreover, external prediction reveals some cases of severe OSC overfitting, which needs attention in future investigations.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"9 1","pages":"3"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73383208","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 : 2002-05-01DOI: 10.1002/1521-3838(200205)21:1<12::AID-QSAR12>3.0.CO;2-M
A. Aptula, T. Netzeva, I. Valkova, M. Cronin, T. Schultz, R. Kühne, G. Schüürmann
A set of 221 phenols, for which toxicity data to the ciliate Tetrahymena pyriformis were available, was subjected to stepwise linear discriminant analysis (LDA) in order to classify their toxic mechanisms of action. The compounds were a priori grouped into the following four mechanisms according to structural rules: polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Hydrophobicity with and without correction for ionisation (log K o w , log D o w u), acidity constant (pK a ), frontier orbital energies (E L U M O , E H O M O ) and hydrogenbond donor and acceptor counts were used as molecular descriptors. LDA models employing 3-6 variables achieved 86-89% overall correct classification of the four mechanisms, with more varied performance for respiratory uncouplers and pro-electrophiles. For the latter, a separate model was developed that discriminated compounds undergoing metabolic activation from compounds with different mechanisms very accurately. Model validation was performed by evaluating the simulated external prediction through LDA models built from complementary subsets.
采用逐步线性判别分析(LDA)对已获得的221种酚类化合物对梨形四膜虫(Tetrahymena pyriformis)的毒性机制进行分类。根据结构规律，将化合物先验地分为极性麻醉剂、弱酸呼吸解偶剂、亲电试剂和软亲电试剂四种机制。疏水性(带或不带电离校正)(log K o w, log D o w)，酸度常数(pK a)，前沿轨道能(E L u M o, E H o M o)和氢键供体和受体计数作为分子描述符。采用3-6个变量的LDA模型对四种机制的分类总体正确率达到86-89%，对呼吸解偶联剂和亲电试剂的分类结果差异较大。对于后者，开发了一个单独的模型，可以非常准确地区分代谢激活的化合物和具有不同机制的化合物。通过互补子集构建的LDA模型对模拟的外部预测进行评估，从而对模型进行验证。
{"title":"Multivariate Discrimination between Modes of Toxic Action of Phenols","authors":"A. Aptula, T. Netzeva, I. Valkova, M. Cronin, T. Schultz, R. Kühne, G. Schüürmann","doi":"10.1002/1521-3838(200205)21:1<12::AID-QSAR12>3.0.CO;2-M","DOIUrl":"https://doi.org/10.1002/1521-3838(200205)21:1<12::AID-QSAR12>3.0.CO;2-M","url":null,"abstract":"A set of 221 phenols, for which toxicity data to the ciliate Tetrahymena pyriformis were available, was subjected to stepwise linear discriminant analysis (LDA) in order to classify their toxic mechanisms of action. The compounds were a priori grouped into the following four mechanisms according to structural rules: polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Hydrophobicity with and without correction for ionisation (log K o w , log D o w u), acidity constant (pK a ), frontier orbital energies (E L U M O , E H O M O ) and hydrogenbond donor and acceptor counts were used as molecular descriptors. LDA models employing 3-6 variables achieved 86-89% overall correct classification of the four mechanisms, with more varied performance for respiratory uncouplers and pro-electrophiles. For the latter, a separate model was developed that discriminated compounds undergoing metabolic activation from compounds with different mechanisms very accurately. Model validation was performed by evaluating the simulated external prediction through LDA models built from complementary subsets.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"8 1","pages":"12-22"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72812162","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 : 2001-12-01DOI: 10.1002/1521-3838(200112)20:5/6<402::AID-QSAR402>3.0.CO;2-6
O. Raevsky, K. Schaper, P. Artursson, J. McFarland
A new approach to predict the intestinal absorption of drugs in humans is presented. It is based on structural similarity and hydrogen bonding properties (ΣC values) of drug-like compounds. The relationship between gastrointestinal absorption in humans and hydrogen bond descriptors for 100 structurally diverse drugs was studied. From the sigmoid relationship for passively transported drugs it could be concluded that those with ΣC values less than 14 were completely absorbed, whereas those with ΣC values higher than 18 were poorly absorbed. In cases where other transport mechanisms prevail due to special structural features, an absorption threshold can be significantly different. So, instead of including the whole set of compounds in the QSAR analyses, small subsets of 1 to 5 structurally related drugs (nearest neighbors of a drug of interest) estimated by means of similarity calculations were considered. The contribution of the passive transport component and the corresponding influence of hydrogen bond factors on absorption was assumed to be similar within the postulated subsets.
{"title":"A Novel Approach for Prediction of Intestinal Absorption of Drugs in Humans based on Hydrogen Bond Descriptors and Structural Similarity","authors":"O. Raevsky, K. Schaper, P. Artursson, J. McFarland","doi":"10.1002/1521-3838(200112)20:5/6<402::AID-QSAR402>3.0.CO;2-6","DOIUrl":"https://doi.org/10.1002/1521-3838(200112)20:5/6<402::AID-QSAR402>3.0.CO;2-6","url":null,"abstract":"A new approach to predict the intestinal absorption of drugs in humans is presented. It is based on structural similarity and hydrogen bonding properties (ΣC values) of drug-like compounds. The relationship between gastrointestinal absorption in humans and hydrogen bond descriptors for 100 structurally diverse drugs was studied. From the sigmoid relationship for passively transported drugs it could be concluded that those with ΣC values less than 14 were completely absorbed, whereas those with ΣC values higher than 18 were poorly absorbed. In cases where other transport mechanisms prevail due to special structural features, an absorption threshold can be significantly different. So, instead of including the whole set of compounds in the QSAR analyses, small subsets of 1 to 5 structurally related drugs (nearest neighbors of a drug of interest) estimated by means of similarity calculations were considered. The contribution of the passive transport component and the corresponding influence of hydrogen bond factors on absorption was assumed to be similar within the postulated subsets.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"24 1","pages":"402-413"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81820105","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 : 2001-12-01DOI: 10.1002/1521-3838(200112)20:5/6<414::AID-QSAR414>3.0.CO;2-V
P. Chavatte, S. Yous, N. Beaurain, C. Mesangeau, G. Ferry, D. Lesieur
The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to a series of 40 compounds synthesized in our laboratory and evaluated as AANAT inhibitors. The N-bromoacetyltryptamine conformation derived from the X-ray crystal structure of the enzyme bound with a bisubstrate analog, was used to obtain the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (30 compounds) and subsequently validated with the corresponding test sets (10 compounds). The best predictive model (n=30, q2=0.644, N=6, r2=0.966, s=0.145, F=109.478) can predict inhibitory activity for a wide range of compounds and offers important structural insight into designing novel AANAT inhibitors prior to their synthesis.
{"title":"Three‐Dimensional Quantitative Structure‐Activity Relationship of Arylalkylamine N‐acetyltransferase (AANAT) Inhibitors: A Comparative Molecular Field Analysis","authors":"P. Chavatte, S. Yous, N. Beaurain, C. Mesangeau, G. Ferry, D. Lesieur","doi":"10.1002/1521-3838(200112)20:5/6<414::AID-QSAR414>3.0.CO;2-V","DOIUrl":"https://doi.org/10.1002/1521-3838(200112)20:5/6<414::AID-QSAR414>3.0.CO;2-V","url":null,"abstract":"The three-dimensional quantitative structure-activity relationship (3D-QSAR) approach using comparative molecular field analysis (CoMFA) was applied to a series of 40 compounds synthesized in our laboratory and evaluated as AANAT inhibitors. The N-bromoacetyltryptamine conformation derived from the X-ray crystal structure of the enzyme bound with a bisubstrate analog, was used to obtain the putative bioactive conformation of these inhibitors. Five statistically significant models were obtained from the randomly constituted training sets (30 compounds) and subsequently validated with the corresponding test sets (10 compounds). The best predictive model (n=30, q2=0.644, N=6, r2=0.966, s=0.145, F=109.478) can predict inhibitory activity for a wide range of compounds and offers important structural insight into designing novel AANAT inhibitors prior to their synthesis.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"150 ","pages":"414-421"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91463293","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 : 2001-12-01DOI: 10.1002/1521-3838(200112)20:5/6<395::AID-QSAR395>3.0.CO;2-#
J. Krysiński, A. Skrzypczak, G. Demski, B. Predki
The relationships between the chemical structure and the antielectrostatic effect of 180 imidazolium chlorides were analysed using the method of rough sets. The antielectrostatic activity was determined by measurements of the surface resistance. Using the rough sets approach the smallest set of condition attributes significant for high quality of classification has been found. The resulting decision rules describe relations between the structure and the antielectrostatic properties of imidazolium chlorides in terms of significant condition attributes. This may be helpful in predicting the structures of the new antielectrostatic compounds to be synthesized.
{"title":"Application of the Rough Set Theory in Structure Activity Relationships of Antielectrostatic Imidazolium Compounds","authors":"J. Krysiński, A. Skrzypczak, G. Demski, B. Predki","doi":"10.1002/1521-3838(200112)20:5/6<395::AID-QSAR395>3.0.CO;2-#","DOIUrl":"https://doi.org/10.1002/1521-3838(200112)20:5/6<395::AID-QSAR395>3.0.CO;2-#","url":null,"abstract":"The relationships between the chemical structure and the antielectrostatic effect of 180 imidazolium chlorides were analysed using the method of rough sets. The antielectrostatic activity was determined by measurements of the surface resistance. Using the rough sets approach the smallest set of condition attributes significant for high quality of classification has been found. The resulting decision rules describe relations between the structure and the antielectrostatic properties of imidazolium chlorides in terms of significant condition attributes. This may be helpful in predicting the structures of the new antielectrostatic compounds to be synthesized.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"7 1","pages":"395-401"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89056999","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 : 2001-12-01DOI: 10.1002/1521-3838(200112)20:5/6<422::AID-QSAR422>3.0.CO;2-Z
M. Holǐk, J. Halámek
Fourier Transform is suggested as a way to change site and substituent oriented variables into new only latently dependent ones. It is possible to find out a model with a low standard error of prediction, SEP%, of activity for not yet prepared compounds. Testing power of the correlation coefficient is improved by calculating a probability, PR, that the regression is made only by chance.
{"title":"Transformation of a Free-Wilson Matrix into Fourier Coefficients","authors":"M. Holǐk, J. Halámek","doi":"10.1002/1521-3838(200112)20:5/6<422::AID-QSAR422>3.0.CO;2-Z","DOIUrl":"https://doi.org/10.1002/1521-3838(200112)20:5/6<422::AID-QSAR422>3.0.CO;2-Z","url":null,"abstract":"Fourier Transform is suggested as a way to change site and\u0000substituent oriented variables into new only latently dependent\u0000ones. It is possible to find out a model with a low standard\u0000error of prediction, SEP%, of activity for not yet prepared\u0000compounds. Testing power of the correlation coefficient is\u0000improved by calculating a probability, PR, that the regression\u0000is made only by chance.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"44 1","pages":"422-428"},"PeriodicalIF":0.0,"publicationDate":"2001-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84192612","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 : 2001-11-01DOI: 10.1002/1521-3838(200111)20:4<291::AID-QSAR291>3.0.CO;2-Q
T. Schelenz, J. Klunker, T. Bernhardt, W. Schäfer, J. Dost
A series of 10 acidic 5-aryl-3H-[1,3,4]oxadiazole-2-thiones was synthesized and characterized with regard to hydrophobic and algistatic properties. Apparent octan-1-ol/water (buffer pH=7.41) partition coefficients (logPapp) were determined by the shake-flask method and used to calculate the partition coefficients of the un-ionized molecules (logPu) on the basis of known pKa values. Relationships between both sets of logP and hydrophobic substituent constants are reported. Biological activity parameters (logA) were derived from growth tests using autotrophic Chlorella vulgaris cultures. The obtained data sets of logA and logP were used in QSAR studies. In this way it could be shown that the algistatic activity of meta- and para-substituted 5-aryl-3H-[1,3,4]-oxadiazole-2-thiones strongly correlates with logPapp, but slightly poorer with logPu. The results are discussed and compared with analogous QSAR/QSPR found for earlier studied series of five-membered N-heterocycles (2-amino-5-aryl-[1,3,4]oxadiazoles, 4-aryl-5-alkyl-2,4-dihydro-[1,2,4]triazol-3-ones, 5-amino-1-aryl-1H-tetrazoles).
{"title":"Relationships between Hydrophobicity and Algistatic Activity of 5‐Aryl‐3H‐[1,3,4]oxadiazole‐2‐thiones","authors":"T. Schelenz, J. Klunker, T. Bernhardt, W. Schäfer, J. Dost","doi":"10.1002/1521-3838(200111)20:4<291::AID-QSAR291>3.0.CO;2-Q","DOIUrl":"https://doi.org/10.1002/1521-3838(200111)20:4<291::AID-QSAR291>3.0.CO;2-Q","url":null,"abstract":"A series of 10 acidic 5-aryl-3H-[1,3,4]oxadiazole-2-thiones was synthesized and characterized with regard to hydrophobic and algistatic properties. \u0000 \u0000 \u0000 \u0000Apparent octan-1-ol/water (buffer pH=7.41) partition coefficients (logPapp) were determined by the shake-flask method and used to calculate the partition coefficients of the un-ionized molecules (logPu) on the basis of known pKa values. Relationships between both sets of logP and hydrophobic substituent constants are reported. \u0000 \u0000 \u0000 \u0000Biological activity parameters (logA) were derived from growth tests using autotrophic Chlorella vulgaris cultures. The obtained data sets of logA and logP were used in QSAR studies. In this way it could be shown that the algistatic activity of meta- and para-substituted 5-aryl-3H-[1,3,4]-oxadiazole-2-thiones strongly correlates with logPapp, but slightly poorer with logPu. \u0000 \u0000 \u0000 \u0000The results are discussed and compared with analogous QSAR/QSPR found for earlier studied series of five-membered N-heterocycles (2-amino-5-aryl-[1,3,4]oxadiazoles, 4-aryl-5-alkyl-2,4-dihydro-[1,2,4]triazol-3-ones, 5-amino-1-aryl-1H-tetrazoles).","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"91 1","pages":"291-297"},"PeriodicalIF":0.0,"publicationDate":"2001-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85542153","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 : 2001-11-01DOI: 10.1002/1521-3838(200111)20:4<319::AID-QSAR319>3.0.CO;2-M
K. Roy, A. De, C. Sengupta
A series of antimalarial cyclic peroxy ketals (n=20) have been subjected to energy minimization using AM1 method, and Wang–Ford charges of the non-hydrogen common atoms (Figure 1), obtained from molecular electrostatic potential surface of the energy minimized geometries, have been used to model the antimalarial activity against P. falciparum. It is found that the difference in charges between the peroxy oxygens contribute positively to the activity, and this is in good agreement with the mode of antimalarial action of the peroxy compounds involving breakage of the peroxy bridge by the haem-iron within the parasite. It is hypothesized that difference in charges between two peroxy oxygens may facilitate the bond breakage. It is further found that the activity increases with increase in negative charge of the methoxy carbon of the common fragment of the molecule. This is related with possible secondary electronic interaction with the positively charged side chains of the histidine rich protein of P. falciparum. Attempt was made to incorporate steric and indicator parameters which emerged as important contributors from previous Hansch analysis. The present results support the previous observations that bulky phenyl ring substituents and a seven-member carbocylic ring attached to the peroxy bridge-containing ring are conducive to the activity.
{"title":"QSAR of Antimalarial Cyclic Peroxy Ketals II: Exploration of Pharmacophoric Site Using AM1 Calculations","authors":"K. Roy, A. De, C. Sengupta","doi":"10.1002/1521-3838(200111)20:4<319::AID-QSAR319>3.0.CO;2-M","DOIUrl":"https://doi.org/10.1002/1521-3838(200111)20:4<319::AID-QSAR319>3.0.CO;2-M","url":null,"abstract":"A series of antimalarial cyclic peroxy ketals (n=20) have been subjected to energy minimization using AM1 method, and Wang–Ford charges of the non-hydrogen common atoms (Figure 1), obtained from molecular electrostatic potential surface of the energy minimized geometries, have been used to model the antimalarial activity against P. falciparum. It is found that the difference in charges between the peroxy oxygens contribute positively to the activity, and this is in good agreement with the mode of antimalarial action of the peroxy compounds involving breakage of the peroxy bridge by the haem-iron within the parasite. It is hypothesized that difference in charges between two peroxy oxygens may facilitate the bond breakage. It is further found that the activity increases with increase in negative charge of the methoxy carbon of the common fragment of the molecule. This is related with possible secondary electronic interaction with the positively charged side chains of the histidine rich protein of P. falciparum. Attempt was made to incorporate steric and indicator parameters which emerged as important contributors from previous Hansch analysis. The present results support the previous observations that bulky phenyl ring substituents and a seven-member carbocylic ring attached to the peroxy bridge-containing ring are conducive to the activity.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"13 1","pages":"319-326"},"PeriodicalIF":0.0,"publicationDate":"2001-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85366290","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 : 2001-11-01DOI: 10.1002/1521-3838(200111)20:4<327::AID-QSAR327>3.0.CO;2-Q
E. Rosines, I. Bersuker, J. E. Boggs
The pharmacophore for group I metabotropic glutamate receptor (mGluRl) agonists is revealed and their activity predicted by means of the previously developed and further improved electron-conformational (EC) method. A distinguishing feature of this method is that in addition to revealing the pharmacophore of activity as a set of specific atomic electronic features arranged in a special geometry, it allows for prediction of the activity quantitatively as a function of the parameters of pharmacophore flexibility and anti-pharmacophore shielding groups. Conformational analysis, electronic structure calculations, and matrix processing are performed for the training set of 29 compounds, 13 active and 16 inactive, and the pharmacophore of mGluRl agonists is evaluated. It contains a four-point skeleton of three oxygen atoms and one nitrogen atom at certain interatomic distances with restricted atomic interaction indices whereby all these parameters are determined within certain tolerances. The pharmacophore parameter flexibilities, as well as the influence of the anti-pharmacophore shielding and other auxiliary groups are parameterized and weighted by seven constants, their values being obtained from a least-square regression with very good statistics: R 2 =0.97, F=589 (∼100% level of confidence), and a standard error of about 5% of the range of measured values. The results are also tested with the leave-one-out cross-validation method that yields prediction statistics R 2 = 0.91. The E statistics were also evaluated illustrating the role of each of the activity parameters involved.
{"title":"Pharmacophore identification and bioactivity prediction for group I metabotropic glutamate receptor agonists by the electron-conformational QSAR method","authors":"E. Rosines, I. Bersuker, J. E. Boggs","doi":"10.1002/1521-3838(200111)20:4<327::AID-QSAR327>3.0.CO;2-Q","DOIUrl":"https://doi.org/10.1002/1521-3838(200111)20:4<327::AID-QSAR327>3.0.CO;2-Q","url":null,"abstract":"The pharmacophore for group I metabotropic glutamate receptor (mGluRl) agonists is revealed and their activity predicted by means of the previously developed and further improved electron-conformational (EC) method. A distinguishing feature of this method is that in addition to revealing the pharmacophore of activity as a set of specific atomic electronic features arranged in a special geometry, it allows for prediction of the activity quantitatively as a function of the parameters of pharmacophore flexibility and anti-pharmacophore shielding groups. Conformational analysis, electronic structure calculations, and matrix processing are performed for the training set of 29 compounds, 13 active and 16 inactive, and the pharmacophore of mGluRl agonists is evaluated. It contains a four-point skeleton of three oxygen atoms and one nitrogen atom at certain interatomic distances with restricted atomic interaction indices whereby all these parameters are determined within certain tolerances. The pharmacophore parameter flexibilities, as well as the influence of the anti-pharmacophore shielding and other auxiliary groups are parameterized and weighted by seven constants, their values being obtained from a least-square regression with very good statistics: R 2 =0.97, F=589 (∼100% level of confidence), and a standard error of about 5% of the range of measured values. The results are also tested with the leave-one-out cross-validation method that yields prediction statistics R 2 = 0.91. The E statistics were also evaluated illustrating the role of each of the activity parameters involved.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"13 1","pages":"327-334"},"PeriodicalIF":0.0,"publicationDate":"2001-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85959270","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 : 2001-11-01DOI: 10.1002/1521-3838(200111)20:4<298::AID-QSAR298>3.0.CO;2-Z
I. DimovDimcho, Z. Nedyalkova, Svetla Haladjova, G. Schüürmann, O. Mekenyan
Rifamycins form a class of antibiotics with a specific potency as drug against tuberculosis via inhibition of the DNA-dependent RNA polymerase. In the present study, literature data on the antibacterial potency against Mycobacterium tuberculosis and other bacteria of 53 derivatives of 3-formyl rifamycin SV are subjected to a QSAR analysis using AM1-based quantum chemical descriptors and the recently introduced dynamic approach that allows explicit consideration of the conformational space of properly generated 3D structures. Data pre-treatment includes normalization of the minimum inhibition concentration (MIC) values of ordinary bacteria using the well-known antituberculosis drug rifampicine as reference compound (RIA), and averaging over the different strains as motivated by a mathematical analysis of the two-step inhibition process. For both this generalized potency against ordinary bacteria and the antimycobacterial activity, QSAR modelling yields 3-variable regression equations with acceptable statistics for screening purposes (r2 around 0.60), which however differ partly in the stepwise-selected molecular descriptors and the respective conformers. While both types of activity are increased by increasing HOMO energy reflecting an increased electron donor capability and tendency to undergo hydroquinone-semiquinone-quinone oxidation, the models differ in the best 2nd and 3rd local quantum chemical descriptors, pointing to partially conflicting electronic structure requirements for optimal antimycobacterial activity and generalized activity against other bacteria. The discussion includes a detailed mechanistic analysis of the underlying bioreactivity aspects.
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