scholarly journals Molecular Docking Guided Grid-Independent Descriptor Analysis to Probe the Impact of Water Molecules on Conformational Changes of hERG Inhibitors in Drug Trapping Phenomenon

2019 ◽  
Vol 20 (14) ◽  
pp. 3385 ◽  
Author(s):  
Saba Munawar ◽  
Jamie I. Vandenberg ◽  
Ishrat Jabeen
Keyword(s):  
Conformational Changes ◽  
External Validation ◽  
3D Qsar ◽  
Drug Binding ◽  
Herg Channel ◽  
Delayed Rectifier ◽  
Water Molecules ◽  
Qsar Models ◽  
Herg Channels ◽  
The Impact

Human ether a-go-go related gene (hERG) or KV11.1 potassium channels mediate the rapid delayed rectifier current (IKr) in cardiac myocytes. Drug-induced inhibition of hERG channels has been implicated in the development of acquired long QT syndrome type (aLQTS) and fatal arrhythmias. Several marketed drugs have been withdrawn for this reason. Therefore, there is considerable interest in developing better tests for predicting drugs which can block the hERG channel. The drug-binding pocket in hERG channels, which lies below the selectivity filter, normally contains K+ ions and water molecules. In this study, we test the hypothesis that these water molecules impact drug binding to hERG. We developed 3D QSAR models based on alignment independent descriptors (GRIND) using docked ligands in open and closed conformations of hERG in the presence (solvated) and absence (non-solvated) of water molecules. The ligand–protein interaction fingerprints (PLIF) scheme was used to summarize and compare the interactions. All models delineated similar 3D hERG binding features, however, small deviations of about ~0.4 Å were observed between important hotspots of molecular interaction fields (MIFs) between solvated and non-solvated hERG models. These small changes in conformations do not affect the performance and predictive power of the model to any significant extent. The model that exhibits the best statistical values was attained with a cryo_EM structure of the hERG channel in open state without water. This model also showed the best R2 of 0.58 and 0.51 for the internal and external validation test sets respectively. Our results suggest that the inclusion of water molecules during the docking process has little effect on conformations and this conformational change does not impact the predictive ability of the 3D QSAR models.

scholarly journals Mechanisms of IhERG/IKr Modulation by α1-Adrenoceptors in HEK293 Cells and Cardiac Myocytes

2016 ◽  
Vol 40 (6) ◽  
pp. 1261-1273 ◽  
Author(s):  
Janire Urrutia ◽  
Aintzane Alday ◽  
Mónica Gallego ◽  
L. Layse Malagueta-Vieira ◽  
Ivan Arael Aréchiga-Figueroa ◽  
...  
Keyword(s):  
Ventricular Fibrillation ◽  
Cardiac Myocytes ◽  
Torsades De Pointes ◽  
Hek293 Cells ◽  
Herg Channel ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
K Current ◽  
Herg Channels ◽  
Intracellular Pathway

Background: The rapid delayed rectifier K+ current (IKr), carried by the hERG protein, is one of the main repolarising currents in the human heart and a reduction of this current increases the risk of ventricular fibrillation. α1-adrenoceptors (α1-AR) activation reduces IKr but, despite the clear relationship between an increase in the sympathetic tone and arrhythmias, the mechanisms underlying the α1-AR regulation of the hERG channel are controversial. Thus, we aimed to investigate the mechanisms by which α1-AR stimulation regulates IKr. Methods: α1-adrenoceptors, hERG channels, auxiliary subunits minK and MIRP1, the non PIP2-interacting mutant D-hERG (with a deletion of the 883-894 amino acids) in the C-terminal and the non PKC-phosphorylable mutant N-terminal truncated-hERG (NTK-hERG) were transfected in HEK293 cells. Cell membranes were extracted by centrifugation and the different proteins were visualized by Western blot. Potassium currents were recorded by the patch-clamp technique. IKr was recorded in isolated feline cardiac myocytes. Results: Activation of the α1-AR reduces the amplitude of IhERG and IKr through a positive shift in the activation half voltage, which reduces the channel availability at physiological membrane potentials. The intracellular pathway connecting the α1-AR to the hERG channel in HEK293 cells includes activation of the Gαq protein, PLC activation and PIP2 hydrolysis, activation of PKC and direct phosphorylation of the hERG channel N-terminal. The PKC-mediated IKr channel phosphorylation and subsequent IKr reduction after α1-AR stimulation was corroborated in feline cardiac myocytes. Conclusions: These findings clarify the link between sympathetic nervous system hyperactivity and IKr reduction, one of the best characterized causes of torsades de pointes and ventricular fibrillation.

scholarly journals Molecular Modeling Studies of Substituted 2,4,5-Trisubstituted Triazolinones Aryl and Nonaryl Derivatives as Angiotensin II AT1Receptor Antagonists

2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Mukesh C. Sharma ◽  
D. V. Kohli ◽  
Smita Sharma
Keyword(s):  
Simulated Annealing ◽  
Statistical Significance ◽  
External Validation ◽  
Feature Selection Method ◽  
3D Qsar ◽  
Field Analysis ◽  
Molecular Field ◽  
Hydrogen Bond Donor ◽  
Molecular Field Analysis ◽  
Qsar Models

The development of new therapies to treat hypertension and cardiovascular diseases. A series of 2,4,5-trisubstituted triazolinones aryl and nonaryl derivatives were subjected toGroup-based QSAR,k-nearest neighbourmolecular field analysis, and pharmacophore mapping. Multiple linear regression (MLR) methodology coupled with feature selection method namely simulated annealing, was applied to derive Group based QSAR models which were further validated for statistical significance and predictive ability by internal and external validation. The best physicochemical descriptors, namely, R1chiV1, R2T_N_O_3, R2chlorines count, R2T_C_N_4, and R2SssNHE index, contribute significantly to the biological activity. The statistically significant best Group-based QSAR model hasr2=0.8357andq2=0.7266with pred_r2=0.8138. The 3D-QSAR studies were performed using the simulated annealing selectionk-nearest neighbormolecular field analysis approach; a leave-one-out cross-validated correlation coefficientq2=0.7461and predicate activity pred_r2=0.7790were obtained. Contour maps using this approach showed that steric, electrostatic, and hydrophobic effects dominantly determine binding affinities. Pharmacophore hypotheses were generated by the mol sign module and found to contain common features like hydrogen bond donor acceptor, donor, positive, negative ionizable, and hydrophobic features. This model can be used for preliminary screening of large number of substituted 3H-1,-2,-4 triazolinone aryl and nonaryl derivatives. The information rendered by 3D-QSAR models may lead to a better understanding of structural requirements of triazolinone aryl and nonaryl derivatives and also aid in designing novel potent antihypertensive molecules.

scholarly journals A Computational Pipeline to Predict Cardiotoxicity

2020 ◽  
Vol 126 (8) ◽  
pp. 947-964 ◽  
Author(s):  
Pei-Chi Yang ◽  
Kevin R. DeMarco ◽  
Parya Aghasafari ◽  
Mao-Tsuen Jeng ◽  
John R.D. Dawson ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Qt Interval ◽  
Channel Model ◽  
Surrogate Marker ◽  
Drug Effects ◽  
Drug Binding ◽  
Herg Channel ◽  
Model Framework ◽  
Drug Induced ◽  
The Impact

Rationale: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. Objective: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. Methods and Results: In a new linkage, we connected atomistic scale information to protein, cell, and tissue scales by predicting drug-binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. Conclusions: We present a multiscale model framework to predict electrotoxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue-level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

scholarly journals Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation

2018 ◽  
Vol 151 (2) ◽  
pp. 231-246 ◽  
Author(s):  
Yu Patrick Shi ◽  
Samrat Thouta ◽  
Yen May Cheng ◽  
Tom W. Claydon
Keyword(s):  
Ph Dependence ◽  
Voltage Sensor ◽  
Herg Channel ◽  
K Channel ◽  
Delayed Rectifier ◽  
Mode Shift ◽  
Deactivation Kinetics ◽  
Shift Behavior ◽  
Activated State ◽  
Herg Channels

hERG channels underlie the delayed-rectifier K+ channel current (IKr), which is crucial for membrane repolarization and therefore termination of the cardiac action potential. hERG channels display unusually slow deactivation gating, which contributes to a resurgent current upon repolarization and may protect against post-depolarization–induced arrhythmias. hERG channels also exhibit robust mode shift behavior, which reflects the energetic separation of activation and deactivation pathways due to voltage sensor relaxation into a stable activated state. The mechanism of relaxation is unknown and likely contributes to slow hERG channel deactivation. Here, we use extracellular acidification to probe the structural determinants of voltage sensor relaxation and its influence on the deactivation gating pathway. Using gating current recordings and voltage clamp fluorimetry measurements of voltage sensor domain dynamics, we show that voltage sensor relaxation is destabilized at pH 6.5, causing an ∼20-mV shift in the voltage dependence of deactivation. We show that the pH dependence of the resultant loss of mode shift behavior is similar to that of the deactivation kinetics acceleration, suggesting that voltage sensor relaxation correlates with slower pore gate closure. Neutralization of D509 in S3 also destabilizes the relaxed state of the voltage sensor, mimicking the effect of protons, suggesting that acidic residues on S3, which act as countercharges to S4 basic residues, are involved in stabilizing the relaxed state and slowing deactivation kinetics. Our findings identify the mechanistic determinants of voltage sensor relaxation and define the long-sought mechanism by which protons accelerate hERG deactivation.

Computational Models for Understanding of Structure, Function and Pharmacology of the Cardiac Potassium Channel Kv11.1 (hERG)

2017 ◽  
Vol 17 (23) ◽  
pp. 2681-2702 ◽  
Author(s):  
Soren Wacker ◽  
Sergei Yu. Noskov ◽  
Laura L. Perissinotti
Keyword(s):  
Action Potential ◽  
Potassium Channel ◽  
Structure Function ◽  
Binding Sites ◽  
Computational Models ◽  
Drug Binding ◽  
Scale Model ◽  
Delayed Rectifier ◽  
Multi Scale ◽  
Herg Channels

The rapid delayed rectifier current I<sub>Kr</sub> is one of the major K+ currents involved in repolarization of the human cardiac action potential. Various inherited or drug-induced forms of the long QT syndrome (LQTS) in humans are linked to functional and structural modifications in the I<sub>Kr</sub> conducting channels. I<sub>Kr</sub> is carried by the potassium channel Kv11.1 encoded by the gene <i>KCNH2</i> (commonly referred to as human ether-a-go-go-related gene or hERG) [1, 2]. The first necessary step for predicting <i>emergent</i> drug effects on the heart is determining and modeling the binding thermodynamics and kinetics of primary and major off-target drug interactions with subcellular targets. The bulk of drugs that target hERG channels are known to have complex interactions at the <i>atomic</i> scale. Accordingly, one of the goals for this review is to provide comprehensive guide in the universe of computational models aiming to refine our understanding of structure-function relations in Kv11.1 and its isoforms. The special emphasis is placed on the mapping of drug binding sites and tentative mechanisms of channel inhibition and activation by drugs. An overview over recent structural models and mapping of binding sites for blockers and activators of I<sub>Kr</sub> current along with the discussion on agreements and discrepancies among different models is presented. There is an apparent reciprocity or feedback loop between drug binding and action potential of the cardiac myocytes. Thus one has to connect drug binding to a particular receptor so that its functional consequences impact on the action potential duration. The natural pathway is to develop multi-scale models that connect between receptor and cellular scales. The potential for such multi-scale model development is discussed through the lens of common gating models. Accordingly, the second part of this review covers an ongoing development of the kinetic models of gating transitions and cardiac ion currents carried by hERG channels with and without drug bound.

Role of glycosylation in cell surface expression and stability of HERG potassium channels

2002 ◽  
Vol 283 (1) ◽  
pp. H77-H84 ◽  
Author(s):  
Qiuming Gong ◽  
Corey L. Anderson ◽  
Craig T. January ◽  
Zhengfeng Zhou
Keyword(s):  
Cell Surface ◽  
Protein Trafficking ◽  
Surface Expression ◽  
Site Directed Mutagenesis ◽  
Herg Channel ◽  
Cell Surface Expression ◽  
Delayed Rectifier ◽  
Channel Stability ◽  
Herg Channels

The human ether-à-go-go-related gene (HERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel in the heart. We previously showed that HERG channel protein is modified by N-linked glycosylation. HERG protein sequence contains two extracellular consensus sites for N-linked glycosylation (N598, N629). In this study, we used the approaches of site-directed mutagenesis and biochemical modification to inhibit N-linked glycosylation and studied the role of glycosylation in the cell surface expression and turnover of HERG channels. Our results show that N598 is the only site for N-linked glycosylation and that glycosylation is not required for the cell surface expression of functional HERG channels. In contrast, N629 is not used for glycosylation, but mutation of this site (N629Q) causes a protein trafficking defect, which results in its intracellular retention. Pulse-chase experiments show that the turnover rate of nonglycosylated HERG channel is faster than that of the glycosylated form, suggesting that N-linked glycosylation plays an important role in HERG channel stability.

scholarly journals Structural modeling of the hERG potassium channel and associated drug interactions

2021 ◽  
Author(s):  
Jan Maly ◽  
Aiyana Emigh ◽  
Kevin DeMarco ◽  
Kazuharu Furutani ◽  
Jon T. Sack ◽  
...  
Keyword(s):  
Potassium Channel ◽  
Conformational Changes ◽  
Drug Binding ◽  
Selectivity Filter ◽  
Herg Channel ◽  
Side Chain ◽  
Ion Conduction ◽  
Drug Induced ◽  
Channel Inactivation ◽  
Conduction Pathway

The voltage-gated potassium channel, KV11.1, encoded by the human Ether-a-go-go-Related Gene (hERG) is expressed in cardiac myocytes, where it is crucial for the membrane repolarization of the action potential. Gating of hERG channel is characterized by rapid, voltage-dependent, C-type inactivation, which blocks ion conduction and is suggested to involve constriction of the selectivity filter. Mutations S620T and S641A/T within the selectivity filter region of hERG have been shown to alter the voltage-dependence of channel inactivation. Because hERG channel blockade is implicated in a number of drug-induced arrhythmias associated with both the open and inactivated states, we simulated the effects of these mutations to elucidate conformational changes associated with hERG channel inactivation and differences in drug binding between the two states. Rosetta modeling of the S641A fast-inactivating mutation revealed a lateral shift of F627 side chain in the selectivity filter into the central channel axis along the ion conduction pathway and formation of a fenestration region below the selectivity filter. Rosetta modeling of the non-inactivating mutations S620T and S641T suggested a potential molecular mechanism preventing F627 side chain from shifting into the ion conduction pathway during the proposed inactivation process. Furthermore, we used Rosetta docking to explore the binding mechanism of highly selective and potent hERG blockers - dofetilide, terfenadine, and E4031. Our results correlate well with existing experimental evidence involving interactions of these drugs with key hERG residues Y652 and F656 inside the pore and reveal potential ligand binding interactions within fenestration region in an inactivated state.

How to Fluorescently Label the Potassium Channel: A Case in hERG

2020 ◽  
Vol 27 (18) ◽  
pp. 3046-3054
Author(s):  
Xiaomeng Zhang ◽  
Beilei Wang ◽  
Zhenzhen Liu ◽  
Yubin Zhou ◽  
Lupei Du
Keyword(s):  
Potassium Channel ◽  
Herg Channel ◽  
Pore Channel ◽  
Design Rationale ◽  
Related Gene ◽  
Open Conformation ◽  
Cardiac Action ◽  
Qt Syndrome ◽  
Herg Channels ◽  
Action Potential Repolarization

hERG (Human ether-a-go-go-related gene) potassium channel, which plays an essential role in cardiac action potential repolarization, is responsible for inherited and druginduced long QT syndrome. Recently, the Cryo-EM structure capturing the open conformation of hERG channel was determined, thus pushing the study on hERG channel at 3.8 Å resolution. This report focuses primarily on summarizing the design rationale and application of several fluorescent probes that target hERG channels, which enables dynamic and real-time monitoring of potassium pore channel affinity to further advance the understanding of the channels.

QSAR Analysis for Antioxidant Activity of Dipicolinic Acid Derivatives

2018 ◽  
Vol 21 (3) ◽  
pp. 204-214 ◽  
Author(s):  
Vesna Rastija ◽  
Maja Molnar ◽  
Tena Siladi ◽  
Vijay Hariram Masand
Keyword(s):  
Antioxidant Activity ◽  
Antioxidant Activities ◽  
Dipicolinic Acid ◽  
External Validation ◽  
Qsar Model ◽  
Internal Validation ◽  
Qsar Analysis ◽  
Dragon Descriptors ◽  
Qsar Models ◽  
New Compounds

Aims and Objectives: The aim of this study was to derive robust and reliable QSAR models for clarification and prediction of antioxidant activity of 43 heterocyclic and Schiff bases dipicolinic acid derivatives. According to the best obtained QSAR model, structures of new compounds with possible great activities should be proposed. Methods: Molecular descriptors were calculated by DRAGON and ADMEWORKS from optimized molecular structure and two algorithms were used for creating the training and test sets in both set of descriptors. Regression analysis and validation of models were performed using QSARINS. Results: The model with best internal validation result was obtained by DRAGON descriptors (MATS4m, EEig03d, BELm4, Mor10p), split by ranking method (R2 = 0.805; R2 ext = 0.833; F = 30.914). The model with best external validation result was obtained by ADMEWORKS descriptors (NDB, MATS5p, MDEN33, TPSA), split by random method (R2 = 0.692; R2 ext = 0.848; F = 16.818). Conclusion: Important structural requirements for great antioxidant activity are: low number of double bonds in molecules; absence of tertial nitrogen atoms; higher number of hydrogen bond donors; enhanced molecular polarity; and symmetrical moiety. Two new compounds with potentially great antioxidant activities were proposed.

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