Pub Date : 2002-08-01DOI: 10.1002/1521-3838(200208)21:3<239::AID-QSAR239>3.0.CO;2-W
K. Schleifer, E. Tot
Three different 3D QSAR methods have been applied for a common pharmacophore model of 45 calcium antagonistically active 1,4-dihydropyridines (DHP) in order to find best correlation of interaction fields and biological activity. Analysis for the entire data set yielded r2/q values in a range starting from 0.821/0.620 (GRID/GOLPE) over 0.872/0.600 (CoMFA) to 0.908/0.744 (CoMSIA). The robustness of these models was tested not only via leave-one-out but also by leave-9-out crossvalidations. Furthermore, models were constructed using a subset of 37 DHPs (training set) allowing the prediction of activity for the residual 8 DHPs (test set). The training set yielded r2/q values starting from 0.826/0.672 (GRID/GOLPE) over 0.872/0.540 (CoMFA) to 0.899/0.662 (CoMSIA). For the test set r values from 0.677 (GRID/GOLPE) over 0.639 (CoMFA) to 0.470 (CoMSIA) were calculated. Besides the statistics, each 3D QSAR model yields further information by analysis of the generated contour maps. Consideration of the CoMFA and CoMSIA fields indicates unfavourable steric interactions for bulky moieties in 4′-position. On the other hand, sterical demanding 2′- and 3′-substituents are favourable and the biological activity of DHPs is further increased if these moieties produce a negative electrostatic potential. In contrast, high π-electron density on top of and parallel to the 4-phenyl ring beside the 2′-position is associated with decreasing activity. This could point to repulsive electronic interactions with binding site residues or to the potential of electron-deficient 4-aryl moieties to behave as electron acceptors in a charge transfer (CT) mechanism.
{"title":"CoMFA, CoMSIA and GRID/GOLPE studies on calcium entry blocking 1,4-dihydropyridines","authors":"K. Schleifer, E. Tot","doi":"10.1002/1521-3838(200208)21:3<239::AID-QSAR239>3.0.CO;2-W","DOIUrl":"https://doi.org/10.1002/1521-3838(200208)21:3<239::AID-QSAR239>3.0.CO;2-W","url":null,"abstract":"Three different 3D QSAR methods have been applied for a common pharmacophore model of 45 calcium antagonistically active 1,4-dihydropyridines (DHP) in order to find best correlation of interaction fields and biological activity. Analysis for the entire data set yielded r2/q values in a range starting from 0.821/0.620 (GRID/GOLPE) over 0.872/0.600 (CoMFA) to 0.908/0.744 (CoMSIA). The robustness of these models was tested not only via leave-one-out but also by leave-9-out crossvalidations. Furthermore, models were constructed using a subset of 37 DHPs (training set) allowing the prediction of activity for the residual 8 DHPs (test set). The training set yielded r2/q values starting from 0.826/0.672 (GRID/GOLPE) over 0.872/0.540 (CoMFA) to 0.899/0.662 (CoMSIA). For the test set r values from 0.677 (GRID/GOLPE) over 0.639 (CoMFA) to 0.470 (CoMSIA) were calculated. Besides the statistics, each 3D QSAR model yields further information by analysis of the generated contour maps. Consideration of the CoMFA and CoMSIA fields indicates unfavourable steric interactions for bulky moieties in 4′-position. On the other hand, sterical demanding 2′- and 3′-substituents are favourable and the biological activity of DHPs is further increased if these moieties produce a negative electrostatic potential. In contrast, high π-electron density on top of and parallel to the 4-phenyl ring beside the 2′-position is associated with decreasing activity. This could point to repulsive electronic interactions with binding site residues or to the potential of electron-deficient 4-aryl moieties to behave as electron acceptors in a charge transfer (CT) mechanism.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"24 1","pages":"239-248"},"PeriodicalIF":0.0,"publicationDate":"2002-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90755644","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<149::AID-QSAR149>3.0.CO;2-#
S. Raugei, Dongsup Kim, M. Klein
We review recent applications of density functional theory based Car-Parrinello molecular dynamics simulations to the study of the structure and reactivity of liquid superacids. We first discuss the nature of an excess proton in liquid hydrofluoric acid, which can be considered as the simplest model of a liquid superacid. Then, we analyze the origin of the superacidity of real superacids in two limiting cases, namely in boron triflouride and antimony pentafluoride in hydrofluoric acid solutions, which are one of the weakest and the strongest known superacids, respectively. We conclude by discussing some aspects of the chemical reactivity of carbon monoxide and simple hydrocarbons in SbF5/HF solutions.
{"title":"Application of Density Functional Theory Based Car-Parrinello Simulations to the Study of Catalytic Processes","authors":"S. Raugei, Dongsup Kim, M. Klein","doi":"10.1002/1521-3838(200207)21:2<149::AID-QSAR149>3.0.CO;2-#","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<149::AID-QSAR149>3.0.CO;2-#","url":null,"abstract":"We review recent applications of density functional theory based Car-Parrinello molecular dynamics simulations to the study of the structure and reactivity of liquid superacids. We first discuss the nature of an excess proton in liquid hydrofluoric acid, which can be considered as the simplest model of a liquid superacid. Then, we analyze the origin of the superacidity of real superacids in two limiting cases, namely in boron triflouride and antimony pentafluoride in hydrofluoric acid solutions, which are one of the weakest and the strongest known superacids, respectively. We conclude by discussing some aspects of the chemical reactivity of carbon monoxide and simple hydrocarbons in SbF5/HF solutions.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"173 1","pages":"149-165"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81899192","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<128::AID-QSAR128>3.0.CO;2-B
F. Bernardi, A. Bottoni, M. Garavelli
In this review we report the results of DFT investigations which have been carried out in different fields of organic and organometallic chemistry, including radical reactivity, structure and reactivity of organometallic compounds, and biochemical/biophysical properties of long chain unsaturated systems. Many of the most popular non-local corrected functionals (e.g. B3LYP, BHLYP, BLYP, BP86) have been benchmarked both versus experimental and high level ab initio (e.g. MP2, MP4, CAS-SCF/CAS-PT2) data, resulting in an impressive agreement. The DFT approach appears to be a powerful tool, which can be used as a valid alternative to more traditional correlated methods, to achieve mechanistic information of chemical/ physical interest in the modelling of organic and biochemical systems. In particular, in the examples selected in this review, we discuss the results obtained for the addition reaction of alkyl radicals to double bonds and for the hydrogen/ chlorine abstraction reaction by alkyl and silyl radicals from various organic substrates. Moreover, binding interactions (i.e. geometries and energies) in organometallic compounds are shown to be satisfactorily reproduced via DFT and examples of nickel-catalyzed [2 + 2] cycloaddition reaction and homogeneous Ziegler-Natta catalysis are investigated. Finally, a DFT modelling for the singlet-oxygen quenching ability and radical trapping activity of carotenes is presented. The simulated data provide a rationale for the protective action of carotenes observed in biological tissues and elucidates the physical and chemical mechanisms involved in the reactivity of carotenes versus oxygen and radicals.
{"title":"Exploring Organic Chemistry with DFT: Radical, Organo‐metallic, and Bio‐organic Applications","authors":"F. Bernardi, A. Bottoni, M. Garavelli","doi":"10.1002/1521-3838(200207)21:2<128::AID-QSAR128>3.0.CO;2-B","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<128::AID-QSAR128>3.0.CO;2-B","url":null,"abstract":"In this review we report the results of DFT investigations which have been carried out in different fields of organic and organometallic chemistry, including radical reactivity, structure and reactivity of organometallic compounds, and biochemical/biophysical properties of long chain unsaturated systems. Many of the most popular non-local corrected functionals (e.g. B3LYP, BHLYP, BLYP, BP86) have been benchmarked both versus experimental and high level ab initio (e.g. MP2, MP4, CAS-SCF/CAS-PT2) data, resulting in an impressive agreement. The DFT approach appears to be a powerful tool, which can be used as a valid alternative to more traditional correlated methods, to achieve mechanistic information of chemical/ physical interest in the modelling of organic and biochemical systems. In particular, in the examples selected in this review, we discuss the results obtained for the addition reaction of alkyl radicals to double bonds and for the hydrogen/ chlorine abstraction reaction by alkyl and silyl radicals from various organic substrates. Moreover, binding interactions (i.e. geometries and energies) in organometallic compounds are shown to be satisfactorily reproduced via DFT and examples of nickel-catalyzed [2 + 2] cycloaddition reaction and homogeneous Ziegler-Natta catalysis are investigated. Finally, a DFT modelling for the singlet-oxygen quenching ability and radical trapping activity of carotenes is presented. The simulated data provide a rationale for the protective action of carotenes observed in biological tissues and elucidates the physical and chemical mechanisms involved in the reactivity of carotenes versus oxygen and radicals.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"27 1","pages":"128-148"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73030445","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<173::AID-QSAR173>3.0.CO;2-B
M. Sulpizi, G. Folkers, U. Rothlisberger, P. Carloni, L. Scapozza
With the advances in genomics, proteomics and functional genomics new therapeutic targets to be tackled by medicinal chemistry are expected. This article reviews applications of first principle methods to address medicinal chemistry issue related to drug/target interactions. Two selected representative case studies involving therapeutically interesting targets are presented. The first case study presents how DFT can contribute to ameliorate scoring functions for drug screening in particular by enabling the discrimination between inhibitors and substrates. The second example shows the use of DFT within the framework of a QM/MM mixed approach for elucidating mechanisms of reaction. This approach allows defining the electronic state and structure of the reaction transition state whose knowledge is essential for designing potent and specific transition state analogs inhibitors. Finally, addressing the issue of other medicinal chemistry related application of DFT we suggest that DFT has indeed the potentiality of becoming very important for challenging new issues presented to medicinal chemistry in the post genomic era.
{"title":"Applications of density functional theory-based methods in medicinal chemistry","authors":"M. Sulpizi, G. Folkers, U. Rothlisberger, P. Carloni, L. Scapozza","doi":"10.1002/1521-3838(200207)21:2<173::AID-QSAR173>3.0.CO;2-B","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<173::AID-QSAR173>3.0.CO;2-B","url":null,"abstract":"With the advances in genomics, proteomics and functional genomics new therapeutic targets to be tackled by medicinal chemistry are expected. This article reviews applications of first principle methods to address medicinal chemistry issue related to drug/target interactions. Two selected representative case studies involving therapeutically interesting targets are presented. The first case study presents how DFT can contribute to ameliorate scoring functions for drug screening in particular by enabling the discrimination between inhibitors and substrates. The second example shows the use of DFT within the framework of a QM/MM mixed approach for elucidating mechanisms of reaction. This approach allows defining the electronic state and structure of the reaction transition state whose knowledge is essential for designing potent and specific transition state analogs inhibitors. Finally, addressing the issue of other medicinal chemistry related application of DFT we suggest that DFT has indeed the potentiality of becoming very important for challenging new issues presented to medicinal chemistry in the post genomic era.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"3 1","pages":"173-181"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82028754","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<97::AID-QSAR97>3.0.CO;2-6
R. Car
Density-Functional-Theory (DFT) provides a general framework to deal with the ground-state energy of the electrons in many-atom systems. Its history dates back to the work of Thomas [1], Fermi [2] and Dirac [3] who devised approximate expressions for the kinetic energy [1, 2] and the exchange energy [3] of many-electron systems in terms of simple functionals of the local electron density. These ideas were further elaborated in the Xα method of Slater [4], until finally, the foundations of the modern theory were laid down in the mid-sixties by Kohn and collaborators [5, 6]. Since then but particularly in the last two decades the number of applications of DFT to electronic structure problems has grown dramatically. Today DFT is the method of choice for first-principles electronic structure calculations in condensed phase and complex molecular environments. DFT based approaches are used in a variety of disciplines ranging from condensed matter physics, to chemistry, materials science, biochemistry and biophysics. There are several reason for this success: (i) DFT makes the many-body electronic problem tractable at a numerical cost of self-consistent-field single particle calculations; (ii) despite the severe approximations made to the exchange and correlation energy functional, DFT calculations are usually sufficiently accurate to predict materials structures or chemical reactions products; (iii) currently available computational power and modern numerical algorithms make DFT calculations feasible for realistic models of systems like e.g. an interface between two crystalline materials, a carbon nanotube, or the active site of an enzyme.
{"title":"Introduction to density-functional theory and ab-initio molecular dynamics","authors":"R. Car","doi":"10.1002/1521-3838(200207)21:2<97::AID-QSAR97>3.0.CO;2-6","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<97::AID-QSAR97>3.0.CO;2-6","url":null,"abstract":"Density-Functional-Theory (DFT) provides a general framework to deal with the ground-state energy of the electrons in many-atom systems. Its history dates back to the work of Thomas [1], Fermi [2] and Dirac [3] who devised approximate expressions for the kinetic energy [1, 2] and the exchange energy [3] of many-electron systems in terms of simple functionals of the local electron density. These ideas were further elaborated in the Xα method of Slater [4], until finally, the foundations of the modern theory were laid down in the mid-sixties by Kohn and collaborators [5, 6]. Since then but particularly in the last two decades the number of applications of DFT to electronic structure problems has grown dramatically. Today DFT is the method of choice for first-principles electronic structure calculations in condensed phase and complex molecular environments. DFT based approaches are used in a variety of disciplines ranging from condensed matter physics, to chemistry, materials science, biochemistry and biophysics. There are several reason for this success: (i) DFT makes the many-body electronic problem tractable at a numerical cost of self-consistent-field single particle calculations; (ii) despite the severe approximations made to the exchange and correlation energy functional, DFT calculations are usually sufficiently accurate to predict materials structures or chemical reactions products; (iii) currently available computational power and modern numerical algorithms make DFT calculations feasible for realistic models of systems like e.g. an interface between two crystalline materials, a carbon nanotube, or the active site of an enzyme.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"69 1","pages":"97-104"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"72898754","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<166::AID-QSAR166>3.0.CO;2-3
P. Carloni
Density functional theory based molecular dynamics (DFT-MD), play an increasingly important role for the modeling of biological systems. Here we outline the principles of the DFT-MD method. Subsequently, we present selected applications in nucleic acid and enzyme chemistry, which are meant to illustrate the power and current limitations of the DFT-MD method for biomolecular simulation.
{"title":"Density Functional Theory‐Based Molecular Dynamics of Biological Systems","authors":"P. Carloni","doi":"10.1002/1521-3838(200207)21:2<166::AID-QSAR166>3.0.CO;2-3","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<166::AID-QSAR166>3.0.CO;2-3","url":null,"abstract":"Density functional theory based molecular dynamics (DFT-MD), play an increasingly important role for the modeling of biological systems. Here we outline the principles of the DFT-MD method. Subsequently, we present selected applications in nucleic acid and enzyme chemistry, which are meant to illustrate the power and current limitations of the DFT-MD method for biomolecular simulation.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"13 1","pages":"166-172"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90494519","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<105::AID-QSAR105>3.0.CO;2-V
V. Barone, O. Crescenzi, R. Improta
The impact of density functional theory in the computation of reliable spectroscopic parameters is reviewed with special reference to IR, Raman, UV, visible, NMR and EPR techniques. In general terms, the results delivered by the most recent density functionals (especially hybrid ones) are remarkably accurate. Proper treatment of solvent effects by continuum models and of vibrational averaging effects by suitable Hamiltonians governing the nuclear motions, significantly increases the reliability of the results and the fields of application of theoretical computations. Some case examples have been reported to better illustrate the potentialities of this approach also for non specialists.
{"title":"Computation of spectroscopic parameters in vacuo and in condensed phases by methods based on the density functional theory","authors":"V. Barone, O. Crescenzi, R. Improta","doi":"10.1002/1521-3838(200207)21:2<105::AID-QSAR105>3.0.CO;2-V","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<105::AID-QSAR105>3.0.CO;2-V","url":null,"abstract":"The impact of density functional theory in the computation of reliable spectroscopic parameters is reviewed with special reference to IR, Raman, UV, visible, NMR and EPR techniques. In general terms, the results delivered by the most recent density functionals (especially hybrid ones) are remarkably accurate. Proper treatment of solvent effects by continuum models and of vibrational averaging effects by suitable Hamiltonians governing the nuclear motions, significantly increases the reliability of the results and the fields of application of theoretical computations. Some case examples have been reported to better illustrate the potentialities of this approach also for non specialists.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"12 1","pages":"105-118"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83471693","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 : 2002-07-01DOI: 10.1002/1521-3838(200207)21:2<119::AID-QSAR119>3.0.CO;2-B
L. Guidoni, P. Maurer, S. Piana, U. Rothlisberger
The theoretical modelling of chemically active transition metal (TM) centres is a notoriously difficult task. The metal-ligand interactions in these complexes are often highly directional and the concoction of suitable analytic interaction potentials can be far from trivial. The situation is rendered even more difficult by the fact that at finite temperature, the system might switch dynamically between different bonding situations or exhibit several energetically close-lying spin states which are all characterized by different coordination numbers and geometries. In this article, we describe the structural, dynamical and reactive properties of complex TM-containing systems with the help of a mixed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics approach, in which the TM centre is described with generalized gradient corrected density functional theory embedded in a classical force field description. The power of such a combined Car-Parrinello/molecular mechanics approach is illustrated with a number of representative examples ranging from enantioselective TM catalysts to radiopharmaceuticals and metalloenzymes.
{"title":"Hybrid Car-Parrinello/molecular mechanics modelling of transition metal complexes: Structure, dynamics and reactivity","authors":"L. Guidoni, P. Maurer, S. Piana, U. Rothlisberger","doi":"10.1002/1521-3838(200207)21:2<119::AID-QSAR119>3.0.CO;2-B","DOIUrl":"https://doi.org/10.1002/1521-3838(200207)21:2<119::AID-QSAR119>3.0.CO;2-B","url":null,"abstract":"The theoretical modelling of chemically active transition metal (TM) centres is a notoriously difficult task. The metal-ligand interactions in these complexes are often highly directional and the concoction of suitable analytic interaction potentials can be far from trivial. The situation is rendered even more difficult by the fact that at finite temperature, the system might switch dynamically between different bonding situations or exhibit several energetically close-lying spin states which are all characterized by different coordination numbers and geometries. In this article, we describe the structural, dynamical and reactive properties of complex TM-containing systems with the help of a mixed quantum mechanical/molecular mechanical (QM/MM) molecular dynamics approach, in which the TM centre is described with generalized gradient corrected density functional theory embedded in a classical force field description. The power of such a combined Car-Parrinello/molecular mechanics approach is illustrated with a number of representative examples ranging from enantioselective TM catalysts to radiopharmaceuticals and metalloenzymes.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"8 1","pages":"119-127"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78575842","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<38::AID-QSAR38>3.0.CO;2-J
M. Appell, Aleksej Krunic, Tony Jeen Choi, S. Mariappan, W. Dunn, M. Reith
We have used the recently developed tensor decomposition 3D-QSAR method to predict the conformation and alignment of cocaine derivatives bound to the monoamine transporters, NET, DAT and SERT. The analysis revealed that the ligands bind to the receptors in a conformation with the 3β-aryl group orthogonal or approximately orthogonal to the tropane ring. Semi rigid ligands have been prepared with a 3β-aryl group having strong conformational preferences for this orientation. Two compounds had affinities for the DAT and SERT in the low nanomolar range. The solution conformation of one compound has been determined and the results support the results of the 3D-QSAR analysis. Comparisons of affinities and selectivities of these ligands are discussed.
{"title":"NMR Study of Conformational Preferences of Inhibitors of Monoamine Uptake","authors":"M. Appell, Aleksej Krunic, Tony Jeen Choi, S. Mariappan, W. Dunn, M. Reith","doi":"10.1002/1521-3838(200205)21:1<38::AID-QSAR38>3.0.CO;2-J","DOIUrl":"https://doi.org/10.1002/1521-3838(200205)21:1<38::AID-QSAR38>3.0.CO;2-J","url":null,"abstract":"We have used the recently developed tensor decomposition 3D-QSAR method to predict the conformation and alignment of cocaine derivatives bound to the monoamine transporters, NET, DAT and SERT. The analysis revealed that the ligands bind to the receptors in a conformation with the 3β-aryl group orthogonal or approximately orthogonal to the tropane ring. Semi rigid ligands have been prepared with a 3β-aryl group having strong conformational preferences for this orientation. Two compounds had affinities for the DAT and SERT in the low nanomolar range. The solution conformation of one compound has been determined and the results support the results of the 3D-QSAR analysis. Comparisons of affinities and selectivities of these ligands are discussed.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"225 1","pages":"38-40"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74465006","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<23::AID-QSAR23>3.0.CO;2-E
P. Japertas, R. Didziapetris, A. Petrauskas
Fragmental methods (FMs) have great potential in many practical areas related to the design of new lead compounds. Advanced Algorithm BuilderTM (AAB) is a new software system which employs FMs in (i) building QSPR, QSAR and SAR models, (ii) converting them to custom (in-house) algorithms and screening filters, and (iii) predicting physical properties and biological activities for new compounds. This review demonstrates how FMs and AAB can be used to substantiate our intuition, interpret observations, validate hypotheses and obtain new algorithms for predicting physical properties and biological activities. Applications for practical and theoretical chemists in the design of new lead compounds are discussed.
{"title":"Fragmental Methods in the Design of New Compounds. Applications of The Advanced Algorithm Builder","authors":"P. Japertas, R. Didziapetris, A. Petrauskas","doi":"10.1002/1521-3838(200205)21:1<23::AID-QSAR23>3.0.CO;2-E","DOIUrl":"https://doi.org/10.1002/1521-3838(200205)21:1<23::AID-QSAR23>3.0.CO;2-E","url":null,"abstract":"Fragmental methods (FMs) have great potential in many practical areas related to the design of new lead compounds. Advanced Algorithm BuilderTM (AAB) is a new software system which employs FMs in (i) building QSPR, QSAR and SAR models, (ii) converting them to custom (in-house) algorithms and screening filters, and (iii) predicting physical properties and biological activities for new compounds. This review demonstrates how FMs and AAB can be used to substantiate our intuition, interpret observations, validate hypotheses and obtain new algorithms for predicting physical properties and biological activities. Applications for practical and theoretical chemists in the design of new lead compounds are discussed.","PeriodicalId":20818,"journal":{"name":"Quantitative Structure-activity Relationships","volume":"26 1","pages":"23-37"},"PeriodicalIF":0.0,"publicationDate":"2002-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81851446","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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