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Schleifer, Klaus‐Jürgen; Tot, Edith

doi:10.1023/a:1015037800903

Cited by 9 publications

(1 citation statement)

References 22 publications

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“…Subsequently, we applied molecular modeling techniques in order to explore the high affinity of the new structures toward the diltiazem binding site and to confirm or refine the recent hypotheses concerning its structural features. In fact, in recent years several SAR studies and quantitative models have been proposed in order to understand the binding mode of calcium antagonists and to propose receptor site schemes for all the three major antagonist classes, that is, BTZs, − DHPs, , and PAAs . Despite the abundance of models regarding DHP-type, little information is available concerning the binding mode of BTZ diltiazem analogues.…”

Section: Introductionmentioning

confidence: 99%

A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

et al. 2005

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In the framework of the continuing interest of this research group in the use of 8-aryl-8-hydroxy-8H-[1,4]thiazino[3,4-c][1,2,4]oxadiazol-3-ones (1) as calcium entry blockers, a number of acetals were synthesized and assayed "in vitro". All of them are structurally related to diltiazem and pyrrolobenzothiazines. The effect on the biological profile was measured by functional assays for a wide variety of acetal residues: saturated linear and branched chains, short and long unsaturated E and/or Z chains as well as benzyl and methylcyclohexyl residues. From selective assays on the most active derivative (5b) (EC(50) = 0.04 microM), which is 20 times more active than diltiazem (EC(50) = 0.79 microM), a muscarinic or adenosinic mechanism of action was excluded. A 3D QSAR model was obtained and validated with homologous literature data, and a virtual receptor scheme was derived for the unknown binding site. The following pharmacophoric features favorably affect the potency: one positively charged center, three lipophilic groups, and two hydrogen-bonding acceptor groups.

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Section: Introductionmentioning

confidence: 99%

A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

et al. 2005

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Prediction of transporter family from protein sequence by support vector machine approach

et al. 2005

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Transporters play key roles in cellular transport and metabolic processes, and in facilitating drug delivery and excretion. These proteins are classified into families based on the transporter classification (TC) system. Determination of the TC family of transporters facilitates the study of their cellular and pharmacological functions. Methods for predicting TC family without sequence alignments or clustering are particularly useful for studying novel transporters whose function cannot be determined by sequence similarity. This work explores the use of a machine learning method, support vector machines (SVMs), for predicting the family of transporters from their sequence without the use of sequence similarity. A total of 10,636 transporters in 13 TC subclasses, 1914 transporters in eight TC families, and 168,341 nontransporter proteins are used to train and test the SVM prediction system. Testing results by using a separate set of 4351 transporters and 83,151 nontransporter proteins show that the overall accuracy for predicting members of these TC subclasses and families is 83.4% and 88.0%, respectively, and that of nonmembers is 99.3% and 96.6%, respectively. The accuracies for predicting members and nonmembers of individual TC subclasses are in the range of 70.7-96.1% and 97.6-99.9%, respectively, and those of individual TC families are in the range of 60.6-97.1% and 91.5-99.4%, respectively. A further test by using 26,139 transmembrane proteins outside each of the 13 TC subclasses shows that 90.4-99.6% of these are correctly predicted. Our study suggests that the SVM is potentially useful for facilitating functional study of transporters irrespective of sequence similarity.

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1,4-Oxazepines and 1,4-Thiazepines

Dehaen

Ngo

2008

Comprehensive Heterocyclic Chemistry III

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Abstract: Based on these molecular descriptors, the quinazolinone derivative MCI-176 is predicted to be a potential ligand of the diltiazem binding site.

Cited by 9 publications

References 22 publications

A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

A New Class of Selective Myocardial Calcium Channel Modulators. 2. Role of the Acetal Chain in Oxadiazol-3-one Derivatives

Prediction of transporter family from protein sequence by support vector machine approach

1,4-Oxazepines and 1,4-Thiazepines

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