scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Therapeutic Efficacy ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Voltage Dependent ◽  
Life Threatening ◽  
Approved Drugs

AbstractCardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD) either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs, a slowly activating K+ current plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage sensing domain (VSD) of the IKs channel. Here we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.Significance statementC28, identified by in silico screening, specifically facilitated voltage dependent activation of a cardiac potassium ion channel, IKs. C28 reversed drug-induced prolongation of action potentials, but minimally affected the normal action potential at the same dosage. This outcome supports a computational prediction of modulating IKs activation as a potential therapy for all forms of action potential prolongation, and could expand therapeutic efficacy of many currently approved drugs that may trigger arrhythmias.

scholarly journals Modulating the voltage sensor of a cardiac potassium channel shows antiarrhythmic effects

2021 ◽  
Vol 118 (20) ◽  
pp. e2024215118
Author(s):  
Yangyang Lin ◽  
Sam Z. Grinter ◽  
Zhongju Lu ◽  
Xianjin Xu ◽  
Hong Zhan Wang ◽  
...  
Keyword(s):  
Action Potential ◽  
Torsade De Pointes ◽  
Computational Prediction ◽  
Chemical Library ◽  
Drug Induced ◽  
Life Threatening ◽  
Approved Drugs ◽  
Voltage Sensing Domain ◽  
Action Potential Repolarization ◽  
Antiarrhythmic Effects

Cardiac arrhythmias are the most common cause of sudden cardiac death worldwide. Lengthening the ventricular action potential duration (APD), either congenitally or via pathologic or pharmacologic means, predisposes to a life-threatening ventricular arrhythmia, Torsade de Pointes. IKs (KCNQ1+KCNE1), a slowly activating K+ current, plays a role in action potential repolarization. In this study, we screened a chemical library in silico by docking compounds to the voltage-sensing domain (VSD) of the IKs channel. Here, we show that C28 specifically shifted IKs VSD activation in ventricle to more negative voltages and reversed the drug-induced lengthening of APD. At the same dosage, C28 did not cause significant changes of the normal APD in either ventricle or atrium. This study provides evidence in support of a computational prediction of IKs VSD activation as a potential therapeutic approach for all forms of APD prolongation. This outcome could expand the therapeutic efficacy of a myriad of currently approved drugs that may trigger arrhythmias.

Cardiovascular Safety of Psychiatric Agents: A Cautionary Tale

Angiology ◽  
2018 ◽  
Vol 70 (2) ◽  
pp. 103-129 ◽  
Author(s):  
Theodora A. Manolis ◽  
Antonis A. Manolis ◽  
Antonis S. Manolis
Keyword(s):  
Psychiatric Patients ◽  
Torsade De Pointes ◽  
Close Monitoring ◽  
Drug Induced ◽  
The Metabolic Syndrome ◽  
Psychotropic Agents ◽  
Individualized Approach ◽  
Life Threatening ◽  
Coronary Syndromes ◽  
Therapy Modification

Psychiatric agents are among the most commonly prescribed medications. Despite the advent of newer generation agents, patients receiving them still experience cardiovascular (CV) side effects. However, these agents may have heterogeneous properties, calling for an individualized approach based on efficacy and also on the particular side effect profile of each specific agent. Proarrhythmic effects arising from drug-induced long-QT syndrome and consequent potentially life-threatening polymorphic ventricular arrhythmias in the form of torsade de pointes, the metabolic syndrome contributing to atherosclerosis and acute coronary syndromes, and drug-induced orthostatic hypotension raise major concerns. Of course, it is also crucial that fear of potential CV adverse effects does not deprive psychiatric patients of appropriate drug therapy. Modification of CV risk factors in psychiatric patients together with optimal management of their CV diseases and appropriate selection of psychotropic agents with greater efficacy and least CV toxicity are of paramount importance in mitigating CV risks and enhancing safety. Identifying patients at high risk of CV complications and close monitoring of all patients receiving these agents are crucial steps to prevent and manage such complications. All these issues are herein reviewed, relevant guidelines are discussed, and schemas are depicted that illustrate the interrelated connections among the psychotropic agents and their CV effects.

In Silico Prediction of Torsadogenic Drug-Induced Proarrhythmias from Action Potential Waveforms in O'Hara-Rudy Human Cardiac Ventricular Model

2017 ◽  
Vol 88 ◽  
pp. 182
Author(s):  
Tetsuji Itoh ◽  
Chiaki Nakamori ◽  
Shota Saiki ◽  
Yuichi Utsumi ◽  
Shigeyuki Fujimoto ◽  
...  
Keyword(s):  
Action Potential ◽  
In Silico ◽  
In Silico Prediction ◽  
Drug Induced

scholarly journals The anesthetic bupivacaine induces cardiotoxicity by targeting L-type voltage-dependent calcium channels

2020 ◽  
Vol 48 (8) ◽  
pp. 030006052094261
Author(s):  
YaNan Gao ◽  
Bo Chen ◽  
Xue Zhang ◽  
Rui Yang ◽  
QingLi Hua ◽  
...  
Keyword(s):  
Patch Clamp ◽  
Action Potential ◽  
Neonatal Rat ◽  
Sprague Dawley ◽  
Patch Clamp Recording ◽  
Drug Induced ◽  
Multifunctional Protein ◽  
Ventricular Cells ◽  
Sprague Dawley Rats ◽  
Voltage Dependent

Objective Bupivacaine is an amide local anesthetic with possible side effects that include an irregular heart rate. However, the mechanism of bupivacaine-induced cardiotoxicity has not been fully elucidated, thus we aimed to examine this mechanism. Methods We performed electrocardiogram recordings to detect action potential waveforms in Sprague Dawley rats after application of bupivacaine, while calcium (Ca2+) currents in neonatal rat ventricular cells were examined by patch clamp recording. Western blot and quantitative real-time polymerase chain reaction assays were used to detect the expression levels of targets of interest. Results In the present study, after application of bupivacaine, abnormal action potential waveforms were detected in Sprague Dawley rats by electrocardiogram recordings, while decreased Ca2+ currents were confirmed in neonatal rat ventricular cells by patch clamp recording. These alterations may be attributed to a deficiency of CaV1.3 (L-type) Ca2+ channels, which may be regulated by the multifunctional protein calreticulin. Conclusions The present study identifies a possible role of the calreticulin–CaV1.3 axis in bupivacaine-induced abnormal action potentials and Ca2+ currents, which may lead to a better understanding anesthetic drug-induced cardiotoxicity.

scholarly journals SARS-COV-2 Spike Glycoprotein as Inhibitory Target for In silico Screening of Natural Compounds

2021 ◽  
Vol 11 (6) ◽  
pp. 14974-14985
Keyword(s):  
In Silico ◽  
Md Simulation ◽  
Simulation Analysis ◽  
Binding Pocket ◽  
Natural Compounds ◽  
Spike Glycoprotein ◽  
Life Threatening ◽  
Inhibitory Potential ◽  
The Stability ◽  
Approved Drugs

Coronavirus disease (Covid-19) caused by SARS-Cov-2 has raised global health concerns without approved drugs to manage this life-threatening disease. This study aimed to predict the inhibitory potential of quercetin-3-o-rutinoside against SARS-Cov-2 spike glycoprotein. Targeting the SARS-Cov-2 Nucleocapsid spike glycoprotein (pdb id: 6m3m) is gaining importance. In this present study, the relationship between plant-derived natural drug and spike glycoprotein was predicted using in silico computational approach. The results were evaluated according to the glide (Schrodinger) dock score. Among the five (5) screened natural compounds, quercetin-3-o-rutinoside has the best docking score (-9.296) with the target. Molecular dynamic (MD) simulation analysis was performed for 1000ps to confirm the spike protein's stability behavior and quercetin-3-o-rutinoside complex. The MD simulation analysis validated the stability of quercetin-3-o-rutinoside in the spike protein binding pocket as a potent inhibitor. The pharmacokinetics screening of the natural compounds showed that quercetin-3-o-rutinoside possesses good oral bioavailability with no side effects.

scholarly journals Deep learning analysis of drug-induced ECG changes to inform arrhythmia risk and improve diagnosis of congenital long QT syndrome

2021 ◽  
Author(s):  
Edi Prifti ◽  
Ahmad Fall ◽  
Giovanni Davogustto ◽  
Alfredo Pulini ◽  
Isabelle Denjoy ◽  
...  
Keyword(s):  
Comprehensive Evaluation ◽  
Torsade De Pointes ◽  
Original Method ◽  
Limited Information ◽  
Long Qt ◽  
Drug Induced ◽  
Life Threatening ◽  
Electrocardiogram Ecg ◽  
Learning Analysis ◽  
Congenital Long Qt Syndrome

Abstract Congenital or drug-induced long-QT syndromes can cause Torsade-de-Pointes (TdP), a life-threatening ventricular arrhythmia. The current strategy to identify individuals at high risk of TdP consists on measuring the QT duration on the electrocardiogram (ECG), shown to provide limited information. We propose an original method, including training deep neural networks to recognize ECG alterations induced by QT-prolonging drugs, as a comprehensive evaluation of TdP risk. These models accurately detected patients taking QT prolonging drugs during ECGs, while discriminating for the presence and type of congenital long-QT. Moreover, they enhanced prediction of drug-induced TdP events in addition to QT measurement. Analyses of these models revealed footprints of the torsadogenic risk and clinically relevant patient stratification.

Comparison of in silico action potential modeling (AP-Predict) and the hiPSc-CM MEA assay in predicting drug-induced cardiotoxicity

2019 ◽  
Vol 99 ◽  
pp. 106595
Author(s):  
Shuya Wang ◽  
Patricia A. Valentine ◽  
Matthew J. Cato ◽  
Anthony Bahinski ◽  
Khuram W. Chaudhary
Keyword(s):  
Action Potential ◽  
In Silico ◽  
Drug Induced

Gold-Aptamer-Nanoconstructs Engineered to Detect Conserved Enteroviral Nucleic Acid Sequences

2019 ◽  
Author(s):  
Veeren Chauhan ◽  
Mohamed M Elsutohy ◽  
C Patrick McClure ◽  
Will Irving ◽  
Neil Roddis ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
In Silico ◽  
Point Of Care ◽  
Lateral Flow ◽  
Nucleic Acid Sequence ◽  
In Silico Screening ◽  
Lateral Flow Assays ◽  
Life Threatening ◽  
Software And Hardware ◽  
Nucleic Acid Sequences

<p>Enteroviruses are a ubiquitous mammalian pathogen that can produce mild to life-threatening disease. Bearing this in mind, we have developed a rapid, accurate and economical point-of-care biosensor that can detect a nucleic acid sequences conserved amongst 96% of all known enteroviruses. The biosensor harnesses the physicochemical properties of gold nanoparticles and aptamers to provide colourimetric, spectroscopic and lateral flow-based identification of an exclusive enteroviral RNA sequence (23 bases), which was identified through in silico screening. Aptamers were designed to demonstrate specific complementarity towards the target enteroviral RNA to produce aggregated gold-aptamer nanoconstructs. Conserved target enteroviral nucleic acid sequence (≥ 1x10<sup>-7</sup> M, ≥1.4×10<sup>-14</sup> g/mL), initiates gold-aptamer-nanoconstructs disaggregation and a signal transduction mechanism, producing a colourimetric and spectroscopic blueshift (544 nm (purple) > 524 nm (red)). Furthermore, lateral-flow-assays that utilise gold-aptamer-nanoconstructs were unaffected by contaminating human genomic DNA, demonstrated rapid detection of conserved target enteroviral nucleic acid sequence (< 60 s) and could be interpreted with a bespoke software and hardware electronic interface. We anticipate our methodology will translate in-silico screening of nucleic acid databases to a tangible enteroviral desktop detector, which could be readily translated to related organisms. This will pave-the-way forward in the clinical evaluation of disease and complement existing strategies at overcoming antimicrobial resistance.</p>

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