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Schmetzer, Silke; Greenidge, Paulette A.; Kovar, Karl‐Artur; Schulze-Alexandru, Meike; Folkers, Gerd

doi:10.1023/a:1007960712989

Cited by 22 publications

(12 citation statements)

References 12 publications

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“…The three-dimensional coordinates of the cannabinoid pharmacophore were kindly provided by Dr. Paulette A. Greenidge (cf. ref ). All ligand molecules were reoptimized in aqueous solution using the AMBER force field as implemented in MacroModel 5.0 …”

Section: Resultsmentioning

confidence: 99%

Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

Vedani¹,

Dobler²,

Zbinden³

1998

J. Am. Chem. Soc.

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A "quasi-atomistic receptor model" refers to a three-dimensional receptor surface, populated with atomistic properties (hydrogen bonds, salt bridges, hydrophobic particles, and solvent) mapped onto it. In contrast to other 3D-QSAR approaches, an algorithm developed at our laboratory allows for the adaptation of the receptor-surface defining envelope to the topology of the individual ligand molecules. In addition, it includes H-bond flip-flop particles which can simultaneously act as H-bond donors and H-bond acceptors toward different ligand molecules, binding to the surrogate within a pharmacophore hypothesis. Such particles mimic aminoacid residues able to engage in differently directed H-bonds at the true biological receptor. Ligand-receptor interaction energies are evaluated using a directional force field for hydrogen bonds and salt bridges. On the basis of a series of ligand molecules with individually adapted receptor envelopes, the software Quasar allows a family of receptor models to be generated using a genetic algorithm combined with cross-validation. Our concept has been used to derive semiquantitative structure-activity relationships for the β2-adrenergic, aryl hydrocarbon, cannabinoid, neurokinin-1, and sweet-taste receptor as well as for the enzyme carbonic anhydrase. The receptor surrogates for these systems are able to predict free energies of ligand binding for independent sets of test ligand molecules within 0.4-0.8 kcal/mol (RMS) of the experimental value.

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Section: Resultsmentioning

confidence: 99%

Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

Vedani¹,

Dobler²,

Zbinden³

1998

J. Am. Chem. Soc.

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“…CoMFA studies have been carried out to develop the 3D-QSAR models of the different classes of cannabinoid ligands for their cannabinoid receptor binding profiles. These efforts include classical and nonclassical cannabinoids, , aminoalkylindoles, eicosanoids, , and arylpyrazoles . Most of these 3D-QSAR studies were focused on the CB1 receptor, − whereas only one study has reported CoMFA models for both CB1 and CB2 receptors .…”

Section: Introductionmentioning

confidence: 99%

“…These efforts include classical and nonclassical cannabinoids, , aminoalkylindoles, eicosanoids, , and arylpyrazoles . Most of these 3D-QSAR studies were focused on the CB1 receptor, − whereas only one study has reported CoMFA models for both CB1 and CB2 receptors . This study used the same training set of 20 compounds with representatives from all five classes of cannabinergic ligands.…”

Section: Introductionmentioning

confidence: 99%

3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. A Combined NMR and CoMFA Approach

et al. 2005

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The present work focuses on the study of the three-dimensional (3D) structural requirements for selective antagonist activity of arylpyrazole compounds at the cannabinoid CB1 and CB2 receptors. Initially, a combined high-resolution two-dimensional (2D) NMR and computer modeling approach was carried out to study the solution structure of the key pyrazole derivative N-(piperidin-1-yl)-5-phenyl-1-(n-pentyl)-4-methyl-1H-pyrazole-3-carboxamide (AM263). By using the NMR-determined molecular conformers as templates, the 3D quantitative structure-activity relationship (QSAR) studies were performed with the comparative molecular field analysis (CoMFA) approach on a set of arylpyrazole cannabinoid receptor antagonists. Molecular alignments suitable for deriving valuable pharmacophoric features for this series of compounds were determined. Such systematic 3D-QSAR/CoMFA analyses of 29 molecules and their receptor affinities gave guidance for understanding the binding affinities of arylpyrazoles at the CB1 and CB2 binding sites, respectively. Comparison of CoMFA steric and potential contour maps for affinity at the two cannabinoid receptor subtypes helps to differentiate structural requirements for each subtype and serves as a basis for the design of later-generation analogues.

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“…Structure−activity analysis is the foundation for understanding structural features of both the inhibitors and the target receptors responsible for biological activity and helps to design more effective inhibitors. , Several 3D quantitative structure−activity relationship (QSAR) studies based on comparative molecular field analysis (CoMFA) have been described (only a few of which are listed here). − The availability of X-ray crystal structures of inhibitors bound with the receptor may contribute to formulating effective predictive 3D-QSAR models as it helps (1) to identify possible bioactive conformations of related inhibitors in the active site and (2) to visualize in three dimensions the interactions of the inhibitors with the receptor. More than 150 HIV-1 protease structures have been solved, most of which are from pharmaceutical companies .…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Quantitative Structure−Activity Relationship Study on Cyclic Urea Derivatives as HIV-1 Protease Inhibitors: Application of Comparative Molecular Field Analysis

Debnath

1999

J. Med. Chem.

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Three-dimensional quantitative structure-activity relationship (3D-QSAR) models have been developed using comparative molecular field analysis (CoMFA) on a large data set (118 compounds) of diverse cyclic urea derivatives as protease inhibitors against the human immunodeficiency virus type 1 (HIV-1). X-ray crystal structures of HIV-1 protease bound with this class of inhibitors were used to derive the most probable bioactive conformations of the inhibitors. The enzyme active site was used as a constraint to limit the number of possible conformations that are sterically accessible. The test sets have been created keeping in mind structural diversity as well as the uniform simple statistical criteria (mean, standard deviation, high and low values) of the protease inhibitory activities of the molecules compared to the training sets. Multiple predictive models have been developed with the training sets (93 compounds in each set) and validated with the corresponding test sets (25 compounds in each set). All the models yielded high predictive correlation coefficients (q2 from 0.699 to 0.727), substantially high fitted correlation coefficients (r2 from 0.965 to 0.973), and reasonably low standard errors of estimates (S from 0. 239 to 0.265). The steric and electrostatic effects have approximately equal contributions, 45% and 55% (approximately), respectively, toward explaining protease inhibitory activities. This analysis yielded models with significant information on steric and electrostatic interactions clearly discerned by the respective coefficient contour plots when overlapped on the X-ray structure of the HIV-1 protease. The HINT CoMFA study revealed significant contribution of hydrophobicity toward protease inhibitory activity. The 3D visualization technique utilizing these contour plots as well as the receptor site geometry may significantly improve our understanding of the inhibitor-protease (HIV-1) interactions and help in designing compounds with improved activity.

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Untitled

Cited by 22 publications

References 12 publications

Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

Quasi-Atomistic Receptor Surface Models: A Bridge between 3-D QSAR and Receptor Modeling

3D-QSAR Studies of Arylpyrazole Antagonists of Cannabinoid Receptor Subtypes CB1 and CB2. A Combined NMR and CoMFA Approach

Three-Dimensional Quantitative Structure−Activity Relationship Study on Cyclic Urea Derivatives as HIV-1 Protease Inhibitors: Application of Comparative Molecular Field Analysis

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