A comparison of HERG channel blocking activities by β-blockers -implication for clinical strategy-

Nagatomo, Toshihisa; Kawakami, Kyojiro; Kikuchi, Kan; Takemasa, Hiroko; Oginosawa, Yasushi; Tsurugi, Takuo; Abe, Haruhiko; Nakashima, Yasuhide

doi:10.1016/j.hrthm.2005.02.551

Cited by 2 publications

(4 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overlay blocker scaffolds to our drain-plug model, and identify the BC, BP, and BY features. Increase the de-solvation cost (reflected in the polarity [33,34]) of these features to slow kon (especially BY, when present), while maintaining on-target activity.…”

Section: )mentioning

confidence: 99%

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Wan

Selvaggio

Pearlstein

2020

Preprint

View full text Add to dashboard Cite

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (IKr). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: 1) Diffusion of a single fully solvated blocker copy into a large cavity lined by the intracellular cyclic nucleotide binding homology domain (the initial capture step). Occupation of this cavity is a necessary but insufficient condition for ion current disruption.2) Translocation of the captured blocker along the channel axis (the IKr disruption step), such that:a) The head group, consisting of a quasi-linear moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface. b) One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost). c) Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region. d) A single captured blocker molecule may associate and dissociate from the pore many times before exiting the CNBHD cavity.Lastly, we highlight possible flaws in the current hERG safety index (SI) and propose an alternate in vivo-relevant strategy factoring in: 1) Benefit/risk.2) The predicted arrhythmogenic fractional hERG occupancy (based on action potential simulations of the undiseased human ventricular cardiomyocyte).3) Alteration of the safety threshold due to underlying disease. 4) Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.As is widely appreciated throughout the pharmaceutical industry, the risk of torsade de pointes arrhythmia (TdP) is promoted by drug-induced loss of function of the human ether-a-go-go gene product (hERG) [1][2][3][4] in proportion to the concomitant fractional decrease in the outward repolarizing hERG current (denoted IKr) due to dynamic blocker occupancy. TdP arises at a threshold level of IKr reduction, which may auto-extinguish spontaneously or progress to ventricular fibrillation and death [5][6][7][8]. The causal relationship between acquired loss of hERG function and TdP was deduced in the l...

show abstract

Section: )mentioning

confidence: 99%

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Wan

Selvaggio

Pearlstein

2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Significant decrease in the percent inhibition/occupancy of a given blocker analog resulting from: k on slowing due to increased blocker de-solvation cost incurred during association via the addition of (or increased polarity of) a polar BC, BP, or BY blocker group (especially BY). Examples of reduced hERG activity putatively due to increased polarity are available in [ 38 ] and [ 39 ]. k off speeding due to decreased blocker re-solvation cost during dissociation via the deletion of (or decreased polarity of) a polar BC, BP, or BY blocker group (especially BY).…”

Section: Resultsmentioning

confidence: 99%

“…k on slowing due to increased blocker de-solvation cost incurred during association via the addition of (or increased polarity of) a polar BC, BP, or BY blocker group (especially BY). Examples of reduced hERG activity putatively due to increased polarity are available in [ 38 ] and [ 39 ].…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Wan¹,

Selvaggio²,

Pearlstein³

2020

PLoS ONE

View full text Add to dashboard Cite

The human ether-a-go-go-related voltage-gated cardiac ion channel (commonly known as hERG) conducts the rapid outward repolarizing potassium current in cardiomyocytes (I Kr ). Inadvertent blockade of this channel by drug-like molecules represents a key challenge in pharmaceutical R&D due to frequent overlap between the structure-activity relationships of hERG and many primary targets. Building on our previous work, together with recent cryo-EM structures of hERG, we set about to better understand the energetic and structural basis of promiscuous blocker-hERG binding in the context of Biodynamics theory. We propose a two-step blocker binding process consisting of: The initial capture step: diffusion of a single fully solvated blocker copy into a large cavity lined by the intra-cellular cyclic nucleotide binding homology domain (CNBHD). Occupation of this cavity is a necessary but insufficient condition for ion current disruption. The I Kr disruption step: translocation of the captured blocker along the channel axis, such that: The head group, consisting of a quasi-rod-shaped moiety, projects into the open pore, accompanied by partial de-solvation of the binding interface. One tail moiety packs along a kink between the S6 helix and proximal C-linker helix adjacent to the intra-cellular entrance of the pore, likewise accompanied by mutual de-solvation of the binding interface (noting that the association barrier is comprised largely of the total head + tail group de-solvation cost). Blockers containing a highly planar moiety that projects into a putative constriction zone within the closed channel become trapped upon closing, as do blockers terminating prior to this region. A single captured blocker copy may conceivably associate and dissociate to/from the pore many times before exiting the CNBHD cavity. Lastly, we highlight possible flaws in the current hERG safety index (SI), and propose an alternate in vivo -relevant strategy factoring in: Benefit/risk. The predicted arrhythmogenic fractional hERG occupancy (based on action potential (AP) simulations of the undiseased human ventricular cardiomyocyte). Alteration of the safety threshold due to underlying disease. Risk of exposure escalation toward the predicted arrhythmic limit due to patient-to-patient pharmacokinetic (PK) variability, drug-drug interactions, overdose, and use for off-label indications in which the hERG safety parameters may differ from their on-label counterparts.

show abstract

A comparison of HERG channel blocking activities by β-blockers -implication for clinical strategy-

Cited by 2 publications

References 0 publications

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Towardin vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Toward in vivo-relevant hERG safety assessment and mitigation strategies based on relationships between non-equilibrium blocker binding, three-dimensional channel-blocker interactions, dynamic occupancy, dynamic exposure, and cellular arrhythmia

Contact Info

Product

Resources

About