Understanding the Structure−Activity Relationship of the Human Ether-a-go-go-Related Gene Cardiac K<sup>+</sup> Channel. A Model for Bad Behavior

Pearlstein, Robert A.; Vaz, Roy J.; Rampe, David

doi:10.1021/jm0205651

Cited by 157 publications

(112 citation statements)

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“…In this study, molecular weight (M W ), molecular fractional polar surface area (FPSA), and lipophilicity (ALogP) were used. We also calculated the pK a of the most positive basic nitrogen (pK a basic) based on previous pharmacophore models [7,14,15] . These four molecular properties were used as simple molecular descriptors for hERG blockage modeling and were calculated with the "Calculate Molecular Properties" protocol within Discovery Studio (version 3.0; Accelrys, San Diego, CA, USA) and components in Pipeline Pilot (version 7.5; Accelrys, San Diego, CA, USA).…”

Section: Calculation Of Molecular Propertiesmentioning

confidence: 99%

“…Previous studies have revealed that most hERG inhibitors have two main characteristics: hydrophobic groups forming π-π stacking and protonated groups forming cation-π interaction with hERG channel residues [50,51] . It has also been suggested that, with increasing hydrophobicity and molecular diameter, the hERG inhibitory effect of a compound increases [9,37] .…”

Section: Molecular Features Important For Hergmentioning

confidence: 99%

“…In our study, we found that molecules with larger ALogP and M W but smaller FPSA are more likely to be blockers, which could be ascribed to the large pore size in hERG as well as the lipophilic character of the pore cavity [37] . Generally, a nitrogen positive ionizable center has been considered a common feature for many hERG blockers [7,50,51,52] . We calculated the pK a value of the most basic nitrogen of compounds (pK a _basic) and found that the pK a _basic of nonblocking molecules is likely to be zero.…”

Section: Molecular Features Important For Hergmentioning

confidence: 99%

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Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Lü

Yin

et al. 2014

Acta Pharmacol Sin

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Aim: A large number of drug-induced long QT syndromes are ascribed to blockage of hERG potassium channels. The aim of this study was to construct novel computational models to predict compounds blocking hERG channels. Methods: Doddareddy's hERG blockage data containing 2644 compounds were used, which divided into training (2389) and test (255) sets. Laplacian-corrected Bayesian classification models were constructed using Discovery Studio. The models were internally validated with the training set of compounds, and then applied to the test set for validation. Doddareddy's experimentally validated dataset with 60 compounds was used for external test set validation. Results: A Bayesian classification model considering the effects of four molecular properties (M w , PPSA, ALogP and pK a _basic) as well as extended-connectivity fingerprints (ECFP_14) exhibited a global accuracy (91%), parameter sensitivity (90%) and specificity (92%) in the test set validation, and a global accuracy (58%), parameter sensitivity (61%) and specificity (57%) in the external test set validation. Conclusion: The novel model is better than those in the literatures for predicting compounds blocking hERG channels, and can be used for large-scale prediction.

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Section: Calculation Of Molecular Propertiesmentioning

confidence: 99%

Section: Molecular Features Important For Hergmentioning

confidence: 99%

Section: Molecular Features Important For Hergmentioning

confidence: 99%

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Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Lü

Yin

et al. 2014

Acta Pharmacol Sin

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“…In the past few years, several commonly used drugs (e.g. terfenadine, cisapride, sertindole, thioridazine, grepafloxacin) were withdrawn from the market, or their approved use was severely restricted, when it was discovered that they caused arrhythmia or were associated with unexplained sudden death, albeit very infrequently (3). The molecular basis of drug-induced LQTS is block of human ether-a-go-go related gene (hERG) channels that conduct I Kr , the rapid delayed rectifier K ϩ current important for repolarization of cardiac action potentials (4,5).…”

Section: Long Qt Syndrome (Lqts)mentioning

confidence: 99%

Physicochemical Features of the hERG Channel Drug Binding Site

Ghanta

Kauffman

et al. 2004

Journal of Biological Chemistry

262

238

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Blockade of hERG K؉ channels in the heart is an unintentional side effect of many drugs and can induce cardiac arrhythmia and sudden death. It has become common practice in the past few years to screen compounds for hERG channel activity early during the drug discovery process. Understanding the molecular basis of drug binding to hERG is crucial for the rational design of medications devoid of this activity. We previously identified 2 aromatic residues, Tyr-652 and Phe-656, located in the S6 domain of hERG, as critical sites of interaction with structurally diverse drugs. Here, Tyr-652 and Phe-656 were systematically mutated to different residues to determine how the physicochemical properties of the amino acid side group affected channel block by cisapride, terfenadine, and MK-499. The potency for block by all three drugs was well correlated with measures of hydrophobicity, especially the twodimensional approximation of the van der Waals hydrophobic surface area of the side chain of residue 656. For residue 652, an aromatic side group was essential for high affinity block, suggesting the importance of a cation-interaction between Tyr-652 and the basic tertiary nitrogen of these drugs. hERG also lacks a Pro-Val-Pro motif common to the S6 domain of most other voltagegated K ؉ channels. Introduction of Pro-Val-Pro into hERG reduced sensitivity to drugs but also altered channel gating. Together, these findings assign specific residues to receptor fields predicted by pharmacophore models of hERG channel blockers and provide a refined molecular understanding of the drug binding site. Long QT syndrome (LQTS)1 is a disorder of ventricular repolarization that predisposes affected individuals to cardiac arrhythmia and sudden death. Inherited LQTS is caused by mutations in K ϩ or Na ϩ ion channel genes or ankyrin-B (1, 2). Acquired LQTS is more common and can be induced as an unintended and rare side effect of treatment with many structurally diverse medications. In the past few years, several commonly used drugs (e.g. terfenadine, cisapride, sertindole, thioridazine, grepafloxacin) were withdrawn from the market, or their approved use was severely restricted, when it was discovered that they caused arrhythmia or were associated with unexplained sudden death, albeit very infrequently (3). The molecular basis of drug-induced LQTS is block of human ether-a-go-go related gene (hERG) channels that conduct I Kr , the rapid delayed rectifier K ϩ current important for repolarization of cardiac action potentials (4, 5). A reduction in I Kr prolongs the action potential duration of ventricular myocytes, lengthens the QT interval and increases dispersion as measured by ECG recordings, and increases the risk of torsades de pointes, a ventricular tachyarrhythmia that can degenerate into fibrillation and cause sudden death. In a laboratory setting, it is possible to induce arrhythmia in animals with drugs that block voltage-gated K ϩ (Kv) channels other than hERG. However, in clinical practice, drug-induced LQTS is always attributable...

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“…hERG potassium channel is associated with electrical activity of the heart that coordinates with heart's beating and its inhibition leads to major consequences of prolonged QT-syndrome provoking cardiac arrhythmia and sudden death (Pearlstein et al 2003). While highlighting the importance of human immune-deficiency virus (HIV), the protease inhibition potential was additionally computed by utilizing the free online programing of molinspiration (www.molinspiration.com).…”

Section: Computational Pharmacokinetic Studiesmentioning

confidence: 99%

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

Wadood

Ghufran

Hassan

et al. 2016

Pharmaceutical Biology

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Fosmidomycin is a promising DXR inhibitor, which showed safety as well as efficacy against Plasmodium falciparum malaria in clinical trials. However, due to its poor oral bioavailability and non-drug-like properties, the focus of medicinal chemists is to develop inhibitors with improved pharmacological properties. Objective: This study described the computational design of new and potent inhibitors for deoxyxylulose 5-phosphate reductoisomerase and the prediction of their pharmacokinetic and pharmacodynamic properties. Material and methods: A complex-based pharmacophore model was generated from the complex X-ray crystallographic structure of PfDXR using MOE (Molecular Operating Environment). Furthermore, MOE-Dock was used as docking software to predict the binding modes of hits and target enzyme.Results: Finally, 14 compounds were selected as new and potent inhibitors of PfDXR on the basis of pharmacophore mapping, docking score, binding energy and binding interactions with the active site residues of the target protein. The predicted pharmacokinetic properties showed improved permeability by efficiently crossing blood-brain barrier. While, in silico promiscuity binding data revealed that these hits also have the ability to bind with other P. falciparum drug targets. Discussion and conclusion: In conclusion, innovative scaffolds with novel modes of action, improved efficacy and acceptable physiochemical/pharmacokinetic properties were computationally identified.ARTICLE HISTORY

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Understanding the Structure−Activity Relationship of the Human Ether-a-go-go-Related Gene Cardiac K⁺ Channel. A Model for Bad Behavior

Cited by 157 publications

References 20 publications

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Physicochemical Features of the hERG Channel Drug Binding Site

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

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Understanding the Structure−Activity Relationship of the Human Ether-a-go-go-Related Gene Cardiac K+ Channel. A Model for Bad Behavior

Cited by 157 publications

References 20 publications

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Novel Bayesian classification models for predicting compounds blocking hERG potassium channels

Physicochemical Features of the hERG Channel Drug Binding Site

In silico identification of promiscuous scaffolds as potential inhibitors of 1-deoxy- d -xylulose 5-phosphate reductoisomerase for treatment of Falciparum malaria

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Product

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Understanding the Structure−Activity Relationship of the Human Ether-a-go-go-Related Gene Cardiac K⁺ Channel. A Model for Bad Behavior