Antiulcer Agents. 6. Analysis of the in Vitro Biochemical and in Vivo Gastric Antisecretory Activity of Substituted Imidazo[1,2-<i>a</i>]pyridines and Related Analogues Using Comparative Molecular Field Analysis and Hypothetical Active Site Lattice Methodologies

Kaminski, James J.; Doweyko, Arthur M.

doi:10.1021/jm950700s

Cited by 187 publications

(63 citation statements)

References 21 publications

(42 reference statements)

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“…q 2 was enhanced and reached values ranging from 0.650 to 0.752. A q 2 value above 0.3 is a clear indication of a confidence limit greater than 95%, which suggests that probability of chance correlation is very low (< 5%) [70][71]. In addition, s was lowered and ranged between 0.337 and 0.401.…”

Section: D-qsar Analysismentioning

confidence: 97%

Definition of an Uptake Pharmacophore of the Serotonin Transporter Through 3D-QSAR Analysis

Pratuangdejkul

Schneider²,

Jaudon³

et al. 2005

CMC

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The serotonergic system plays a critical role in a wide variety of physiological and behavioral processes. Dysregulation of the tightly controlled extracellular concentration of serotonin (5-hydroxytryptamine, 5-HT) appears to be at the origin of a host of metabolic and psychiatric disorders. Since the plasma membrane 5-HT transporter (SERT) is the major protagonist in regulating extracellular 5-HT concentration, SERT is the target of most drugs interacting with the serotonergic system. Unfortunately, some of the drugs towards SERT (e.g. amphetamine derivatives) interfere with cell homeostasis leading to cell toxicity. Developing new SERT ligands devoid of any side-effect represents a major priority in the treatment of 5-HT-associated pathologies. Here, we report structure-activity relationships (SAR) and three-dimensional QSAR (3D-QSAR) studies of a library of 121 compounds including 5-HT analogs, harmanes, benzothiazoles, indanones, amphetamine derivatives and substrate-type 5-HT releasers, with the goal of identifying the structural determinants crucial for SERT uptake. In the absence of data about the bioactive form of 5-HT, conformational analysis of 5-HT was performed using quantum chemistry calculations. This led to three 5-HT stable conformers with anti, -gauche and +gauche side-chain conformation. These conformers, used as templates for superimposition with all the library compounds, enabled the design of a reliable 6-points pharmacophore representative of SERT uptake activity. Molecular dynamics (MD) simulations performed with compounds that are efficiently, moderately, poorly or not transported by SERT allowed to assess the validity of our pharmacophore. Altogether, our data provide for the first time a reliable pharmacophore of SERT uptake activity, which may help to the design of new drugs targeting SERT.

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Section: D-qsar Analysismentioning

confidence: 97%

Definition of an Uptake Pharmacophore of the Serotonin Transporter Through 3D-QSAR Analysis

Pratuangdejkul

Schneider²,

Jaudon³

et al. 2005

CMC

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“…The bioactivity of a specific compound is forecasted by summing all the partial activity values at points in common with the composite reference lattice. Some of the successful applications of HASL approach include the analysis of the in vitro antimalarial activity of artemisinin analogs [58], in vitro biochemical and in vivo gastric antisecretory activity of substituted imidazo[1,2-a]pyridines [59], sequence specificity of DNA alkylation by uracil mustard [60], and the generation of putative pharmacophoric models of the HIV-1 protease inhibitors [61]. HASL is a copyrighted program of Hypothesis Software and eduSoft LC [62], and also comes as one of the modules in Sybyl Software [33].…”

Section: Haslmentioning

confidence: 99%

3D-QSAR in Drug Design - A Review

Verma¹,

Khedkar²,

Coutinho

2010

CTMC

657

393

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Quantitative structure-activity relationships (QSAR) have been applied for decades in the development of relationships between physicochemical properties of chemical substances and their biological activities to obtain a reliable statistical model for prediction of the activities of new chemical entities. The fundamental principle underlying the formalism is that the difference in structural properties is responsible for the variations in biological activities of the compounds. In the classical QSAR studies, affinities of ligands to their binding sites, inhibition constants, rate constants, and other biological end points, with atomic, group or molecular properties such as lipophilicity, polarizability, electronic and steric properties (Hansch analysis) or with certain structural features (Free-Wilson analysis) have been correlated. However such an approach has only a limited utility for designing a new molecule due to the lack of consideration of the 3D structure of the molecules. 3D-QSAR has emerged as a natural extension to the classical Hansch and Free-Wilson approaches, which exploits the three-dimensional properties of the ligands to predict their biological activities using robust chemometric techniques such as PLS, G/PLS, ANN etc. It has served as a valuable predictive tool in the design of pharmaceuticals and agrochemicals. Although the trial and error factor involved in the development of a new drug cannot be ignored completely, QSAR certainly decreases the number of compounds to be synthesized by facilitating the selection of the most promising candidates. Several success stories of QSAR have attracted the medicinal chemists to investigate the relationships of structural properties with biological activity. This review seeks to provide a bird's eye view of the different 3D-QSAR approaches employed within the current drug discovery community to construct predictive structure-activity relationships and also discusses the limitations that are fundamental to these approaches, as well as those that might be overcome with the improved strategies. The components involved in building a useful 3D-QSAR model are discussed, including the validation techniques available for this purpose.

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“…The consideration of the interior of a molecule according to the characteristics calculated at the lattice point is used in many well-known methods, e.g., in hypotetical active site lattice (HASL) and comparative molecular field analysis (CoMFA) [32][33][34][35]. However, in the ConGO algorithm the structures are considered on the basis of the calculated electron density agreeing closely with the results of highly accurate X-ray analysis, as shown in the next section.…”

Section: Congo Algorithmmentioning

confidence: 99%

A new paradigm for pattern recognition of drugs

Потемкин

Grishina

2008

J Comput Aided Mol Des

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A new paradigm is suggested for pattern recognition of drugs. The approach is based on the combined application of the 4D/3D quantitative structure-activity relationship (QSAR) algorithms BiS and ConGO. The first algorithm, BiS/MC (multiconformational), is used for the search for the conformers interacting with a receptor. The second algorithm, ConGO, has been suggested for the detailed study of the selected conformers' electron density and for the search for the electron structure fragments that determine the pharmacophore and antipharmacophore parts of the compounds. In this work we suggest using a new AlteQ method for the evaluation of the molecular electron density. AlteQ describes the experimental electron density (determined by low-temperature highly accurate X-ray analysis) much better than a number of quantum approaches. Herein this is shown using a comparison of the computed electron density with the results of highly accurate X-ray analysis. In the present study the desirability function is used for the first time for the analysis of the effects of the electron structure in the process of pattern recognition of active and inactive compounds. The suggested method for pattern recognition has been used for the investigation of various sets of compounds such as DNA-antimetabolites, fXa inhibitors, 5-HT(1A), and alpha(1)-AR receptors inhibitors. The pharmacophore and antipharmacophore fragments have been found in the electron structures of the compounds. It has been shown that the pattern recognition cross-validation quality for the datasets is unity.

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Antiulcer Agents. 6. Analysis of the in Vitro Biochemical and in Vivo Gastric Antisecretory Activity of Substituted Imidazo[1,2-a]pyridines and Related Analogues Using Comparative Molecular Field Analysis and Hypothetical Active Site Lattice Methodologies

Cited by 187 publications

References 21 publications

Definition of an Uptake Pharmacophore of the Serotonin Transporter Through 3D-QSAR Analysis

Definition of an Uptake Pharmacophore of the Serotonin Transporter Through 3D-QSAR Analysis

3D-QSAR in Drug Design - A Review

A new paradigm for pattern recognition of drugs

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