Pub Date : 1999-12-01DOI: 10.1002/(SICI)1521-3838(199912)18:6<548::AID-QSAR548>3.0.CO;2-B
Meike Schulze-Alexandru, K. Kovar, A. Vedani
The 5-HT2A receptor is known to act as the biological target for a series of hallucinogenic substances including substituted phenylalkylamines, tryptamines and LSD. A prerequisite for a hallucinogenic effect is an agonistic binding mode to the high-affinity state of the receptor. Attempts to establish a quantitative structure-activity relationship for such compounds are typically based on homology models or 3D-QSAR. In this paper, we describe a surrogate for the 5-HT2A receptor derived by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique. This approach allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena. The QSARs are established based on a family of receptor-surface models, generated by a genetic algorithm combined with cross-validation. The surrogate for the 5-HT2A receptor yielded a cross-validated q 2 of 0.954 for the 23 compounds defining the training set. A series of 7 test compounds was then used to validate the model, resulting in a RMS deviation of 0.40 kcalymol between DG 0 prd. and DG 0 exp.. The largest individual deviation was 0.61 kcaly mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q 2 a 0.144, slopea 7 0.019) demonstrates the sensitivity of the model with respect to the biological data. Subsequently, the surrogate was used to estimate the activity of a series of 53 hypothetical congeneric compounds, some of which are predicted to be close in activity to LSD.
{"title":"Quasi‐atomistic Receptor Surrogates for the 5‐HT2A Receptor: A 3D‐QSAR Study on Hallucinogenic Substances","authors":"Meike Schulze-Alexandru, K. Kovar, A. Vedani","doi":"10.1002/(SICI)1521-3838(199912)18:6<548::AID-QSAR548>3.0.CO;2-B","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199912)18:6<548::AID-QSAR548>3.0.CO;2-B","url":null,"abstract":"The 5-HT2A receptor is known to act as the biological target for a series of hallucinogenic substances including substituted phenylalkylamines, tryptamines and LSD. A prerequisite for a hallucinogenic effect is an agonistic binding mode to the high-affinity state of the receptor. Attempts to establish a quantitative structure-activity relationship for such compounds are typically based on homology models or 3D-QSAR. In this paper, we describe a surrogate for the 5-HT2A receptor derived by means of quasi-atomistic receptor modeling (software Quasar), a more recently developed 3D-QSAR technique. This approach allows for the simulation of local induced fit, H-bond flip-flop, and solvation phenomena. The QSARs are established based on a family of receptor-surface models, generated by a genetic algorithm combined with cross-validation. The surrogate for the 5-HT2A receptor yielded a cross-validated q 2 of 0.954 for the 23 compounds defining the training set. A series of 7 test compounds was then used to validate the model, resulting in a RMS deviation of 0.40 kcalymol between DG 0 prd. and DG 0 exp.. The largest individual deviation was 0.61 kcaly mol, corresponding to an uncertainty of a factor 2.7 in the binding affinity. A scramble test with negative outcome (q 2 a 0.144, slopea 7 0.019) demonstrates the sensitivity of the model with respect to the biological data. Subsequently, the surrogate was used to estimate the activity of a series of 53 hypothetical congeneric compounds, some of which are predicted to be close in activity to LSD.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74407222","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<543::AID-QSAR543>3.0.CO;2-V
E. Polymeropoulos, N. Höfgen
Selective inhibitors of the isoenzyme phosphodiesterase 4 (PDE 4) have attracted increased interest in the last few years as potential drugs for the treatment of allergic diseases such as asthmal,2.
{"title":"A Peptidic Binding Site Model for PDE 4 Inhibitors","authors":"E. Polymeropoulos, N. Höfgen","doi":"10.1002/(SICI)1521-3838(199912)18:6<543::AID-QSAR543>3.0.CO;2-V","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199912)18:6<543::AID-QSAR543>3.0.CO;2-V","url":null,"abstract":"Selective inhibitors of the isoenzyme phosphodiesterase 4 (PDE 4) have attracted increased interest in the last few years as potential drugs for the treatment of allergic diseases such as asthmal,2.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78160382","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<561::AID-QSAR561>3.0.CO;2-V
E. Jacoby, J. Fauchère, E. Raimbaud, Sophie Ollivier, A. Michel, M. Spedding
Three-dimensional models of ligand-receptor complexes based on site-directed mutagenesis experiments of the monoamine G protein-coupled receptors reveal the existence of three distinct drug binding sites inside the receptors. Here, we develop this “three-site” hypothesis and outline its implications for the modular design of ligands for monoamine GPCRs. Molecular models of receptor-ligand complexes are built for the 5-HT1A receptor where mutagenesis studies map three spatially distinct binding regions which correspond to the binding sites of the “small, one site-filling” ligands 5-HT, propranolol and 8-OH-DPAT, respectively. The models of the 5-HT1A ligand-receptor complexes provide a frame for the discussion of other ligand-receptor interactions, including α1 and β2 adrenoceptors, D1 and D2 dopamine, and 5-HT1D and 5-HT2A receptors, where mutagenesis and modelling studies also showed occupation of the corresponding three binding locations. All three binding sites are located within the highly conserved seven helix transmembrane domain of the receptor and overlap partially at the prominent Asp residue in TM3 which constitutes the benchmark anchor site for monoamine ligands. The analysis of the sequence similarity, for each binding site, among the monoamine GPCR superfamily shows that the three loci display different degrees of evolutionary conservation. This result suggests different roles for each of the binding sites in intrinsic receptor functions and provides additional insights for the design of ligand functionality and selectivity. The existence of three distinct binding sites is also reflected by the architecture of known high affinity ligands which crosslink two or three “one site-filling” fragments around a basic amino group. Typical ligands reported in the Cipsline/MDDR portfolio illustrate this point despite the occasional difficulty of attributing the individual ligand fragments to a specific receptor site. The database exploration illustrates the binding site promiscuity of some fragments which is particularly evident for symmetrical ligands and which has implications for 3D QSAR methods dependent on alignments. We propose to generate by deconvolution of known ligands three distinct databases of site-specific bioisosters which should provide keystones for the design of novel recomposed monoamine GPCR ligands. The systematic exploration of the “three site” hypothesis should open novel perspectives for the understanding of ligand recognition for this class of therapeutically important receptors.
{"title":"A Three Binding Site Hypothesis for the Interaction of Ligands with Monoamine G Protein‐coupled Receptors: Implications for Combinatorial Ligand Design","authors":"E. Jacoby, J. Fauchère, E. Raimbaud, Sophie Ollivier, A. Michel, M. Spedding","doi":"10.1002/(SICI)1521-3838(199912)18:6<561::AID-QSAR561>3.0.CO;2-V","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199912)18:6<561::AID-QSAR561>3.0.CO;2-V","url":null,"abstract":"Three-dimensional models of ligand-receptor complexes based on site-directed mutagenesis experiments of the monoamine G protein-coupled receptors reveal the existence of three distinct drug binding sites inside the receptors. Here, we develop this “three-site” hypothesis and outline its implications for the modular design of ligands for monoamine GPCRs. Molecular models of receptor-ligand complexes are built for the 5-HT1A receptor where mutagenesis studies map three spatially distinct binding regions which correspond to the binding sites of the “small, one site-filling” ligands 5-HT, propranolol and 8-OH-DPAT, respectively. The models of the 5-HT1A ligand-receptor complexes provide a frame for the discussion of other ligand-receptor interactions, including α1 and β2 adrenoceptors, D1 and D2 dopamine, and 5-HT1D and 5-HT2A receptors, where mutagenesis and modelling studies also showed occupation of the corresponding three binding locations. All three binding sites are located within the highly conserved seven helix transmembrane domain of the receptor and overlap partially at the prominent Asp residue in TM3 which constitutes the benchmark anchor site for monoamine ligands. The analysis of the sequence similarity, for each binding site, among the monoamine GPCR superfamily shows that the three loci display different degrees of evolutionary conservation. This result suggests different roles for each of the binding sites in intrinsic receptor functions and provides additional insights for the design of ligand functionality and selectivity. The existence of three distinct binding sites is also reflected by the architecture of known high affinity ligands which crosslink two or three “one site-filling” fragments around a basic amino group. Typical ligands reported in the Cipsline/MDDR portfolio illustrate this point despite the occasional difficulty of attributing the individual ligand fragments to a specific receptor site. The database exploration illustrates the binding site promiscuity of some fragments which is particularly evident for symmetrical ligands and which has implications for 3D QSAR methods dependent on alignments. We propose to generate by deconvolution of known ligands three distinct databases of site-specific bioisosters which should provide keystones for the design of novel recomposed monoamine GPCR ligands. The systematic exploration of the “three site” hypothesis should open novel perspectives for the understanding of ligand recognition for this class of therapeutically important receptors.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80264532","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 : 1999-11-01DOI: 10.1002/(SICI)1521-3838(199911)18:5<464::AID-QSAR464>3.0.CO;2-R
R. A. Cercós-del-Pozo, F. Pérez-Giménez, Salabert-Salvador Mt, F. J. García-March, Miguel Murcia-Soler
New compounds showing hypolipaemic activity have been designed using a computer-aided method based on molecular topology and QSAR analysis. Linear discriminant analysis and connectivity functions were used to design three potentially suitable drugs which were tested for hypolipaemic properties by the Triton WR-1339 test in rats. The pharmacological tests carried out on the newly designed compounds demonstrated the existence of notable activity in phase I for two of them. namely 2,6-Di-tert-butyl-4-methylpyridine (C.A.S. 38222-83-2) and 2,6-Di-tert-butylpyridine (C.A.S. 585-48-8), with respect to the level of total cholesterol. Both substances decrease the lipaemia to lower levels than clofibrate, which was used as a reference drug.
{"title":"NEW HYPOLIPAEMIC AGENTS DESIGNED BY MOLECULAR TOPOLOGY : PHARMACOLOGICAL STUDIES OF 2,6-DI-TERT-BUTYL-4-METHYLPYRIDINE AND 2,6-DI-TERT-BUTYLPYRIDINE","authors":"R. A. Cercós-del-Pozo, F. Pérez-Giménez, Salabert-Salvador Mt, F. J. García-March, Miguel Murcia-Soler","doi":"10.1002/(SICI)1521-3838(199911)18:5<464::AID-QSAR464>3.0.CO;2-R","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199911)18:5<464::AID-QSAR464>3.0.CO;2-R","url":null,"abstract":"New compounds showing hypolipaemic activity have been designed using a computer-aided method based on molecular topology and QSAR analysis. Linear discriminant analysis and connectivity functions were used to design three potentially suitable drugs which were tested for hypolipaemic properties by the Triton WR-1339 test in rats. The pharmacological tests carried out on the newly designed compounds demonstrated the existence of notable activity in phase I for two of them. namely 2,6-Di-tert-butyl-4-methylpyridine (C.A.S. 38222-83-2) and 2,6-Di-tert-butylpyridine (C.A.S. 585-48-8), with respect to the level of total cholesterol. Both substances decrease the lipaemia to lower levels than clofibrate, which was used as a reference drug.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78294764","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 : 1999-11-01DOI: 10.1002/(SICI)1521-3838(199911)18:5<482::AID-QSAR482>3.0.CO;2-R
A. Tsantili-Kakoulidou, A. Varvaresou, T. Siatra-Papastaikoudi, O. Raevsky
{"title":"A comprehensive investigation of the partitioning and hydrogen bonding behavior of indole containing derivatives of 1,3,4-thiadiazole and 1,2,4-triazole by means of experimental and calculative approaches","authors":"A. Tsantili-Kakoulidou, A. Varvaresou, T. Siatra-Papastaikoudi, O. Raevsky","doi":"10.1002/(SICI)1521-3838(199911)18:5<482::AID-QSAR482>3.0.CO;2-R","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199911)18:5<482::AID-QSAR482>3.0.CO;2-R","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73360145","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 : 1999-11-01DOI: 10.1002/(SICI)1521-3838(199911)18:5<456::AID-QSAR456>3.0.CO;2-N
M. Feher, K. Kánai, I. Hermecz, A. Lopata, I. Novák
{"title":"A 3D-QSAR analysis of prolyl endopeptidase inhibitors","authors":"M. Feher, K. Kánai, I. Hermecz, A. Lopata, I. Novák","doi":"10.1002/(SICI)1521-3838(199911)18:5<456::AID-QSAR456>3.0.CO;2-N","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199911)18:5<456::AID-QSAR456>3.0.CO;2-N","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84160176","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 : 1999-11-01DOI: 10.1002/(SICI)1521-3838(199911)18:5<474::AID-QSAR474>3.0.CO;2-N
V. Segarra, Manel López, H. Ryder, J. Palacios
{"title":"Prediction of Drug Permeability Based on Grid Calculations","authors":"V. Segarra, Manel López, H. Ryder, J. Palacios","doi":"10.1002/(SICI)1521-3838(199911)18:5<474::AID-QSAR474>3.0.CO;2-N","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199911)18:5<474::AID-QSAR474>3.0.CO;2-N","url":null,"abstract":"","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76745121","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 : 1999-10-01DOI: 10.1002/(SICI)1521-3838(199910)18:4<354::AID-QSAR354>3.0.CO;2-2
K. Schaper
Recently published brain dopamine D2 receptor affinity data of 15 tetrahydroprotoberberine (THPB) derivatives acting as dopamine receptor antagonists have been analyzed by two different QSAR techniques. The following main results were obtained by this analysis: In contrast to an unsuccessful Free-Wilson/Fujita-Ban analysis the investigated receptor binding data could be described by a neural network approach using only binary substructural indicator variables. The artificial/computational neural network was able to recognize that the affinity depends significantly on the simultaneous presence or absence of two or more substituents. A 4-D plot demonstrates the non-additivity/-variability of substituent effects on D2 receptor affinity.
{"title":"FREE-WILSON-TYPE ANALYSIS OF NON-ADDITIVE SUBSTITUENT EFFECTS ON THPB DOPAMINE RECEPTOR AFFINITY USING ARTIFICIAL NEURAL NETWORKS","authors":"K. Schaper","doi":"10.1002/(SICI)1521-3838(199910)18:4<354::AID-QSAR354>3.0.CO;2-2","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199910)18:4<354::AID-QSAR354>3.0.CO;2-2","url":null,"abstract":"Recently published brain dopamine D2 receptor affinity data of 15 tetrahydroprotoberberine (THPB) derivatives acting as dopamine receptor antagonists have been analyzed by two different QSAR techniques. The following main results were obtained by this analysis: In contrast to an unsuccessful Free-Wilson/Fujita-Ban analysis the investigated receptor binding data could be described by a neural network approach using only binary substructural indicator variables. The artificial/computational neural network was able to recognize that the affinity depends significantly on the simultaneous presence or absence of two or more substituents. A 4-D plot demonstrates the non-additivity/-variability of substituent effects on D2 receptor affinity.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82809809","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 : 1999-10-01DOI: 10.1002/(SICI)1521-3838(199910)18:4<329::AID-QSAR329>3.0.CO;2-V
S. Dove, A. Buschauer
More realistic description of ligand-receptor interactions in CoMFA results from alignments considering surface and field properties instead of only molecular frameworks. The field fit algorithm implemented in SYBYL (Tripos Ass.) as part of the energy minimizer provides the possibility to assign individual weights to grid points. A new weighting function derives the significance of grid points for the alignment of fields from preceding CoMFA runs, using regression coefficients, means, and standard deviations of field variables as parameters. Just in strongly diverse congeneric series, the method does not underestimate the common structure and not overweight variable, interacting regions. CoMFA of a large series of 142 histamine H2 receptor agonistic imidazolylpropylguanidines (pD2 values from guinea pig atrium) is presented as example. Results with three different alignments were compared: (1) exact superposition of the constant imidazolylpropylguanidine moiety, (2) SUPERIMPOSE or FIT of energy minima, (3) minimization of the structures by weighted field fit with weights based on CoMFA with alignment 2. A significant improvement of cross-validated PLS results was observed from alignment to alignment: Leave-one-out approach: (1) 7 PC's, Q2=0.59, sPRESS=0.50, (2) 8 PC's, Q2=0.66, sPRESS=0.46, (3) 9 PC's, Q2=0.71, sPRESS=0.42. Cross validation with 10 groups (mean of 10 runs): (1) 6.3 PC's, Q2=0.59, sPRESS=0.50, (2) 6.1 PC's, Q2=0.65, sPRESS=0.47, (3) 9.5 PC's, Q2=0.71, sPRESS=0.43. It is concluded that risks of the field fit method like producing artificial redundancy of the structures and ignoring entropy contributions to the free energy of binding are lowered with the given weighting method.
{"title":"Improved Alignment by Weighted Field Fit in CoMFA of Histamine H2 Receptor Agonistic Imidazolylpropylguanidines","authors":"S. Dove, A. Buschauer","doi":"10.1002/(SICI)1521-3838(199910)18:4<329::AID-QSAR329>3.0.CO;2-V","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199910)18:4<329::AID-QSAR329>3.0.CO;2-V","url":null,"abstract":"More realistic description of ligand-receptor interactions in CoMFA results from alignments considering surface and field properties instead of only molecular frameworks. The field fit algorithm implemented in SYBYL (Tripos Ass.) as part of the energy minimizer provides the possibility to assign individual weights to grid points. A new weighting function derives the significance of grid points for the alignment of fields from preceding CoMFA runs, using regression coefficients, means, and standard deviations of field variables as parameters. Just in strongly diverse congeneric series, the method does not underestimate the common structure and not overweight variable, interacting regions. CoMFA of a large series of 142 histamine H2 receptor agonistic imidazolylpropylguanidines (pD2 values from guinea pig atrium) is presented as example. Results with three different alignments were compared: (1) exact superposition of the constant imidazolylpropylguanidine moiety, (2) SUPERIMPOSE or FIT of energy minima, (3) minimization of the structures by weighted field fit with weights based on CoMFA with alignment 2. A significant improvement of cross-validated PLS results was observed from alignment to alignment: Leave-one-out approach: (1) 7 PC's, Q2=0.59, sPRESS=0.50, (2) 8 PC's, Q2=0.66, sPRESS=0.46, (3) 9 PC's, Q2=0.71, sPRESS=0.42. Cross validation with 10 groups (mean of 10 runs): (1) 6.3 PC's, Q2=0.59, sPRESS=0.50, (2) 6.1 PC's, Q2=0.65, sPRESS=0.47, (3) 9.5 PC's, Q2=0.71, sPRESS=0.43. It is concluded that risks of the field fit method like producing artificial redundancy of the structures and ignoring entropy contributions to the free energy of binding are lowered with the given weighting method.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86587711","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 : 1999-10-01DOI: 10.1002/(SICI)1521-3838(199910)18:4<369::AID-QSAR369>3.0.CO;2-F
I. Pajeva, M. Wiese
The main purpose of the study was to examine the correctness of interpretation of CoMFA results using an artificially designed data set with predefined contributions of the compound substituents to activity. The activity values were assigned according to additive (sum of substituent π-constants) and nonlinear (sum of absolute values of substituent π-constants) dependencies on hydrophobicity. Predictions by 3D (HINT hydrophobic fields) and logP (HINT and CLOGP values) presentations of hydrophobicity were compared and similarity between standard CoMFA and hydrophobic fields was evaluated. The main results are: (i) the cross- validated R2 (Q2) values with the first PLS components of the field models may be indicative for identification of the underlying property(ies) in the data set providing each field alone yields a satisfactory predictive model with several components; (ii) the logP values alone are not predictive when the target property is nonlinearly dependent on the explanatory property; (iii) similarity between fields of different nature (steric, electrostatic, hydrophobic) can be evaluated by cross- and non-cross-validation correlations between the X-scores of the first components – low Q2 and R2 suggest that the most informative variances of the compared fields are different; (iv) the CoMFA graphical display is very much dependent on the distribution of the positive and negative field terms – if their contributions to the whole field signal are not symmetrically distributed the default CoMFA contour view setting can lead to wrong displays and, consequently, wrong interpretation of the results.
{"title":"Interpretation of CoMFA Results – A Probe Set Study Using Hydrophobic Fields","authors":"I. Pajeva, M. Wiese","doi":"10.1002/(SICI)1521-3838(199910)18:4<369::AID-QSAR369>3.0.CO;2-F","DOIUrl":"https://doi.org/10.1002/(SICI)1521-3838(199910)18:4<369::AID-QSAR369>3.0.CO;2-F","url":null,"abstract":"The main purpose of the study was to examine the correctness of interpretation of CoMFA results using an artificially designed data set with predefined contributions of the compound substituents to activity. The activity values were assigned according to additive (sum of substituent π-constants) and nonlinear (sum of absolute values of substituent π-constants) dependencies on hydrophobicity. Predictions by 3D (HINT hydrophobic fields) and logP (HINT and CLOGP values) presentations of hydrophobicity were compared and similarity between standard CoMFA and hydrophobic fields was evaluated. The main results are: (i) the cross- validated R2 (Q2) values with the first PLS components of the field models may be indicative for identification of the underlying property(ies) in the data set providing each field alone yields a satisfactory predictive model with several components; (ii) the logP values alone are not predictive when the target property is nonlinearly dependent on the explanatory property; (iii) similarity between fields of different nature (steric, electrostatic, hydrophobic) can be evaluated by cross- and non-cross-validation correlations between the X-scores of the first components – low Q2 and R2 suggest that the most informative variances of the compared fields are different; (iv) the CoMFA graphical display is very much dependent on the distribution of the positive and negative field terms – if their contributions to the whole field signal are not symmetrically distributed the default CoMFA contour view setting can lead to wrong displays and, consequently, wrong interpretation of the results.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"1999-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79219703","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}
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