QSAR analysis of time-and dose-dependent in vivo drug effects using artificial neural networks

Schapper, Klaus-Jürgen; Wiese, Michael; Dieter, Reinhold; Emig, Peter; Engel, Jürgen; Kutscher, Bernhard; Polymeropoulos, Emmanuel E.

doi:10.1007/978-94-011-1472-1_151

Cited by 3 publications

(3 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Obviously a broad range of activity data facilitates the recognition of QSAR relationships. The evaluation of the IC 50 values for the compounds where only one point of the curve was available was performed by the application of a method, which consists in a simultaneous nonlinear regression analysis of all dose−response curves (DRCs) of the drug series using eq 1 where SU is the specific union of radioligand; b is the slope; i = 1... n (measurements); j: 1...m (number of compounds).…”

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

Benhamú

et al. 1997

J. Med. Chem.

View full text Add to dashboard Cite

A series of 48 bicyclohydantoin-phenylpiperazines (1-4) with affinity for 5-HT1A and alpha 1 receptors was subjected to three-dimensional quantitative structure-affinity relationship analysis using comparative molecular field analysis (CoMFA), in order to get insight into the structural requirements that are responsible for 5-HT1A/alpha 1 selectivity. Good models (high cross-validation correlations and predictive power) were obtained for 5-HT1A and alpha 1 receptors. The resulting 3D-QSAR models rationalize steric and electrostatic factors which modulate binding to 5-HT1A and alpha 1 receptors. A comparison of these models gives an additional understanding for 5-HT1A/alpha 1 selectivity: (a) Substitution at the ortho position by a group with negative potential is favorable to affinity for both receptors. (b) The meta position seems to be implicated in 5-HT1A/alpha 1 selectivity. While the 5-HT1A receptor is able to accommodate bulky substituents in the region of its active site, the steric requirements of the alpha 1 receptor are more restricted (optimum volume of substituent 11-25 A3). (c) For both receptors the para position represents a region where the volume accessible by the ligands is limited. (d) The hydantoin moiety and the side chain length seem to modulate not only the affinity but also 5-HT1A/alpha 1 selectivity. The 3D-QSAR models reveal an useful predictive information for the design of new selective ligands.

show abstract

Section: Methodsmentioning

confidence: 99%

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

Benhamú

et al. 1997

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…The simultaneous analysis of pharmacodynamics and pharmacokinetics of single drugs by ANNs has recently also been published by Veng-Pedersen et al [21,22] and by Gobburu et al [23]. However, with the exception of the analysis of one rather small data set investigated in our group [24] and of a simulation study by Wiese [25] to the best of our knowledge no analysis of the pharmacodynamics-and pharmacokinetics-dependent in vivo effect of sets of compounds has been published. Therefore, in view of the capabilities of ANNs to take complex non-linear relationships into account, it appeared of interest to use this technique in the formulation of QSAR models (including dose, time, and physicochemical descriptors) of the hypotensive activity profile of the above 1- A. K. Saxena and K.-J.…”

Section: Introductionmentioning

confidence: 93%

“…Furthermore, these additional data were processed by applying a higher weight to the corresponding errors (%obsd.-%calc.) as described before [24]. Each chemical structure was described for the three important physicochemical parameters viz.…”

Section: Datamentioning

confidence: 99%

QSAR analysis of the time dependent hypotensive activity of 1‐[3‐(4‐substituted phenylthio)propyl]‐4‐(3,4‐substituted phenyl)piperazines using Artificial Neural Networks

Saxena

Schaper

2003

QSAR Comb. Sci.

View full text Add to dashboard Cite

The quantitative analysis and physicochemical description of time-and dose-dependent in vivo drug effects is problematic as observed effects depend on both pharmacodynamics and pharmacokinetics. These factors depend in a different manner on the physicochemical properties of investigated drugs. Obviously in vivo effects of drug series are governed by highly non-linear and extremely complicated relationships. The exact form of these relations usually can be given only for some restricted experimental conditions and generally may be assumed to be unknown. As the function relating in vivo hypotensive effects of the title compounds observed in cats, to dose, time and physicochemical properties could not be modelled explicitly, an attempt has been made to train an Artificial Neural Network (ANN) to find the unknown non-linear relationship between input variables and observed % effect values (raw data, AE 20 ± 25% error). Although each drug was applied at only two different doses and ™% effect∫ was observed at few time points, the weights characterising the ANN model enabled the calculation/prediction of (i) complete time-activity profiles (reflecting mainly pharmacokinetics); (ii) physicochemical property dependent activities. Thus, a maximum of information was extracted from raw in vivo data by this approach which may be useful in saving animal experiments in drug development. However, complete dose-response curves could not be obtained due to insufficient data in terms of applied doses.

show abstract

QSAR Analysis of the Time‐ and Dose‐Dependent Anti‐Inflammatory in vivo Activity of Substituted Imidazo[1,2‐a]pyridines Using Artificial Neural Networks

Saxena¹,

Schaper²

2006

QSAR Comb. Sci.

View full text Add to dashboard Cite

show abstract

QSAR analysis of time-and dose-dependent in vivo drug effects using artificial neural networks

Cited by 3 publications

References 2 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

QSAR analysis of the time dependent hypotensive activity of 1‐[3‐(4‐substituted phenylthio)propyl]‐4‐(3,4‐substituted phenyl)piperazines using Artificial Neural Networks

QSAR Analysis of the Time‐ and Dose‐Dependent Anti‐Inflammatory in vivo Activity of Substituted Imidazo[1,2‐a]pyridines Using Artificial Neural Networks

Contact Info

Product

Resources

About

QSAR analysis of time-and dose-dependent in vivo drug effects using artificial neural networks

Cited by 3 publications

References 2 publications

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT1A and α1 Receptors. A Comparison of CoMFA Models

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT1A and α1 Receptors. A Comparison of CoMFA Models

QSAR analysis of the time dependent hypotensive activity of 1‐[3‐(4‐substituted phenylthio)propyl]‐4‐(3,4‐substituted phenyl)piperazines using Artificial Neural Networks

QSAR Analysis of the Time‐ and Dose‐Dependent Anti‐Inflammatory in vivo Activity of Substituted Imidazo[1,2‐a]pyridines Using Artificial Neural Networks

Contact Info

Product

Resources

About

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models

Synthesis and Structure−Activity Relationships of a New Model of Arylpiperazines. 2. Three-Dimensional Quantitative Structure−Activity Relationships of Hydantoin−Phenylpiperazine Derivatives with Affinity for 5-HT_1A and α₁ Receptors. A Comparison of CoMFA Models