Toward in vivo relevant drug design

Pearlstein, Robert A.; Wan, Hongbin; Aravamuthan, Vibhas

doi:10.1016/j.drudis.2020.10.012

Cited by 10 publications

(37 citation statements)

References 31 publications

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“…We recently described a first principles physics-based theory (which we refer to as "Biodynamics" [1,21]) describing the general paradigm by which:…”

Section: Discussionmentioning

confidence: 99%

“…We recently described a first principles physics-based theory (which we refer to as “Biodynamics” [1,21]) describing the general paradigm by which: Cellular function (biochemical and electrical) is generated by molecular systems. Molecular systems respond to perturbations. Cellular dysfunction results from molecular dysfunction or excessive perturbation. …”

Section: Discussionmentioning

confidence: 99%

“…As for all cellular systems, the AP generation systems of excitable cells, including cardiomyocytes, operate within the non-equilibrium/non-linear dynamics regime [1]. Stable APs depend on tight dynamic counter-balancing between inward and outward ion currents, such that Δ ψ m ( t ) neither under-nor overshoots into the proarrhythmic range.…”

Section: Introductionmentioning

confidence: 99%

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Probing cellular arrhythmogenesis using the O’Hara-Rudy model of the undiseased human ventricular cardiomyocyte

Selvaggio¹,

Wan²,

Pearlstein³

2020

Preprint

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The ventricular action potential (AP) is subserved by an interdependent system of voltage-gated ion channels and pumps that both alter and respond (directly or indirectly) to the dynamic transmembrane potential (Δψm(t)) via voltage-dependent state transitions governing inward and outward ion currents. The native dynamic inward-outward current balance is subject to disruption caused by acquired or inherited loss or gain of function in one or more ion channels or pumps. Building on our previous work, we used a modified version of the O’Hara-Rudy (ORd) model of the undiseased human ventricular cardiomyocyte to study the pro-arrhythmic effects of three types of arrhythmia-inducing perturbations in midmyocytes (M cells): Blockade of the human ether-a-go-go related gene (hERG) K+ channel introduced via a Markov state binding model.Mutation-induced voltage shifts in hERG channel gating, resulting in faster inactivation or slowed recovery of both phosphorylated and non-phosphorylated forms of the channel (known as LQT2 syndrome).Mutation-induced voltage shifts in Nav1.5 gating, resulting in slowed late inactivation of the phosphorylated and non-phosphorylated forms of the channel (known as LQT3 syndrome).We studied the relationships between ion current anomalies and AP morphology as a function of cycle length (CL) and perturbation type/level. The results are summarized as follows: AP duration (APD) is governed directly by Kir2.1 activation (IK1), which is delayed when repolarization is slowed by abnormal net inward tipping of the dynamic inward-outward current balance (reflected in decreased d(Δψm(t))/dt during the late AP repolarization phase). In the case of hERG blockade by non-trappable compounds, the perturbation level consists of the dynamic fractional occupancy of the channel, which is governed by blocker kon relative to the rate of channel opening, pharmacokinetic exposure, and koff (in that order).Arrhythmia progresses from prolonged paced APs → atypical APs (spontaneous and paced) → self-sustaining oscillations. Abrupt transitions between these regimes occur at CL- and perturbation-specific thresholds (denoted as T1, T2, and T3, respectively), whereas intra-regime progression proceeds in a graded fashion toward the subsequent threshold. APD and d(Δψm(t))/dt during the late repolarization phase varied significantly across the 200 APs of our simulations near the T1 threshold at CL = 1/35 min, reflecting increasing instability of the AP generation system.Arrhythmic APs exhibit highly variable cycle-to-cycle morphologies, depending on the perturbation level, type, and phasing between the underlying ion channel states and pacing cycle.Atypical APs may be triggered by typical or atypical depolarizations prior to the T3 threshold, depending on perturbation type/level and phasing relative to CL: APD/CL resides outside of the Goldilocks zone: APD/CL → 1 at shorter CL and/or longer APD, resulting in pro-arrhythmic “collisions” between successive paced APs (APi and APj) within a given cardiomyocyte. We studied this scenario at 60 and 80 beats per minute (BPM), equating to CL = 1/60 and 1/80 min.APD/CL < 1 at longer CL results in spontaneous atypical depolarizations within prolonged paced APs at elevated takeoff Δψm(t) and increased channel phosphorylation levels. We studied this scenario at CL = 1/35 min.APD and d(Δψm(t))/dt during the late repolarization phase become increasingly variable over successive APs on approach to the T1 threshold, which is the possible source of short-long-short sequences observed in the ECG preceding torsades de pointes arrhythmia (TdP).All atypical depolarizations are solely Cav1.2 (ICa,L)-driven (Δψm(t) falls within the Nav1.5 inactivation window), whereas typical depolarizations are Nav1.5 (INa) + ICa,L-driven. Atypical depolarization versus typical repolarization occurrences are determined by the faster of Cav1.2 and Kir2.1 (IK1) activation (where IK1 becomes increasingly dampened as the minimum Δψm(t) drifts above the Kir2.1 activation window).Cav1.2 inactivation gates reset to the open position (accompanied by recovery) synchronously with channel closing under control conditions, generating a small ICa,L window current in the process. This current grows toward a depolarizing spike when the lag time between recovery and closing grows above a threshold level.APs undergo damped oscillatory Cav1.2 recovery/re-inactivation cycles above the T3 threshold, which are refreshed by subsequent pacing signals (nodal or reentrant in origin).

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“…We recently described a first principles physics-based theory (which we refer to as "Biodynamics" [1,21]) describing the general paradigm by which:…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Probing cellular arrhythmogenesis using the O’Hara-Rudy model of the undiseased human ventricular cardiomyocyte

Selvaggio¹,

Wan²,

Pearlstein³

2020

Preprint

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“…2) The canonical association barrier consists principally of the total desolvation cost of the binding interface (contributed by H-bond enriched solvation), and canonical dissociation barrier consists principally of the cost of resolvating H-bond depleted solvation positions expelled during association [1][2][3][9][10][11][12]. kon is proportional to the degree of replacement of the H-bonds of H-bond enriched solvation expelled during association (noting that the free energy gains from such replacements are typically ≤ the free energy lost from desolvation, resulting at best in a zero sum energy game).…”

Section: Binding Free Energy Is Contributed Principally By Solvation and The Implications Thereof For Herg Blockadementioning

confidence: 99%

“…The copyright holder for this preprint this version posted October 9, 2021. ; https://doi.org/10.1101/2021.10.07.463585 doi: bioRxiv preprint ii. The positions/H-bond propensities of polar groups vis-à-vis H-bond enriched solvation and non-polar groups vis-à-vis H-bond depleted solvation [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

General structure-free energy relationships of hERG blocker binding under native cellular conditions

Wan¹,

Spiru²,

Williams³

et al. 2021

Preprint

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We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water ('the solvation field') relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We analyzed blockade of the ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as 'BP') into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as 'BC') occupying the cytoplasmic 'antechamber' of hERG; and 2) undergo second-order entry to the antechamber, followed by first-order association of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polar pore is solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereas blocker BP moieties are solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, the blocker solvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with blocker potency and Redfern safety classification.

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Mechanistic and data-driven models of cell signaling: Tools for fundamental discovery and rational design of therapy

Myers

Lee

Lazzara

2021

Current Opinion in Systems Biology

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Toward in vivo relevant drug design

Cited by 10 publications

References 31 publications

Probing cellular arrhythmogenesis using the O’Hara-Rudy model of the undiseased human ventricular cardiomyocyte

Probing cellular arrhythmogenesis using the O’Hara-Rudy model of the undiseased human ventricular cardiomyocyte

General structure-free energy relationships of hERG blocker binding under native cellular conditions

Mechanistic and data-driven models of cell signaling: Tools for fundamental discovery and rational design of therapy

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