Digging into Lipid Membrane Permeation for Cardiac Ion Channel Blocker d-Sotalol with All-Atom Simulations

Abstract

Interactions of drug molecules with lipid membranes play crucial role in their accessibility of cellular targets and can be an important predictor of their therapeutic and safety profiles. Very little is known about spatial localization of various drugs in the lipid bilayers, their active form (ionization state) or translocation rates and therefore potency to bind to different sites in membrane proteins. All-atom molecular simulations may help to map drug partitioning kinetics and thermodynamics, thus providing in-depth assessment of drug lipophilicity. As a proof of principle, we evaluated extensively lipid membrane partitioning of d-sotalol, well-known blocker of a cardiac potassium channel Kv11.1 encoded by the hERG gene, with reported substantial proclivity for arrhythmogenesis. We developed the positively charged (cationic) and neutral d-sotalol models, compatible with the biomolecular CHARMM force field, and subjected them to all-atom molecular dynamics (MD) simulations of drug partitioning through hydrated lipid membranes, aiming to elucidate thermodynamics and kinetics of their translocation and thus putative propensities for hydrophobic and aqueous hERG access. We found that only a neutral form of d-sotalol accumulates in the membrane interior and can move across the bilayer within millisecond time scale, and can be relevant to a lipophilic channel access. The computed water-membrane partitioning coefficient for this form is in good agreement with experiment. There is a large energetic barrier for a cationic form of the drug, dominant in water, to cross the membrane, resulting in slow membrane translocation kinetics. However, this form of the drug can be important for an aqueous access pathway through the intracellular gate of hERG. This route will likely occur after a neutral form of a drug crosses the membrane and subsequently re-protonates. Our study serves to demonstrate a first step toward a framework for multi-scale in silico safety pharmacology, and identifies some of the challenges that lie therein.

Atomistic modeling towards predictive cardiotoxicity

“…We also computed the diffusion coefficient, ( ), profiles across the POPC membrane for both forms of the drug, with values in the bulk water, W, of ~6 x10 -6 cm 2 /s for DOFC and ~7 x10 -6 cm 2 /s for DOFN, each attenuating to M <0.5 x10 -6 cm 2 /s at the membrane center ( Figure 2D and Table 1). Such an order of magnitude drop in the diffusion in the membrane interior was observed in our previous studies for ions and other drugs as well (30,34,53). Based on these data, we estimated the membrane translocation rate of neutral dofetilide (see SI Methods) as 7.96 ± 1.37 ms -1 .…”

“…positively charged (Dofetilide(+) or DOFC) dominant drug ionization forms (Figure 2A), which have different polarities, lipophilicities and lipid membrane permeabilities. This was demonstrated in our previous study on the example of another hERG blocking drug sotalol, which has similar functional groups and can also exist in cationic and neutral forms (34). Moreover, neutral and charged forms of a drug likely have different affinities for their protein targets, which was demonstrated in a recent study using hERG homology models and preliminary empirical force field models of dofetilide (33).…”

“…In this study, we show that it is possible to predict drug-channel kinetics from atomicresolution simulations, and hence begin to solve problem of preclinical drug cardiac safety screening in silico. Our current work expands upon our recent investigations (29)(30)(31)(32)(33)(34)(35) into drug and ion channel model development, and drug-channel binding using all-atom MD simulations. For instance, we recently developed and validated atomistic force field models of charged and neutral forms of the local anesthetic and anti-arrhythmic drug lidocaine and determined its preferred binding modalities and pathways in the cardiac voltage-gated sodium (NaV) channel using multi-microsecond long unbiased MD simulations, providing good agreement with available experimental electrophysiology data as well as new structural predictions (35).…”

“…For instance, we recently developed and validated atomistic force field models of charged and neutral forms of the local anesthetic and anti-arrhythmic drug lidocaine and determined its preferred binding modalities and pathways in the cardiac voltage-gated sodium (NaV) channel using multi-microsecond long unbiased MD simulations, providing good agreement with available experimental electrophysiology data as well as new structural predictions (35). In another recent work, we developed force field models of the hERG-blocking drug sotalol, which has high pro-arrhythmia proclivity, and studied its lipid membrane partitioning using both unbiased and enhanced sampling MD simulations, obtaining reasonably accurate energetics and kinetics of drug -lipid bilayer interactions (34).…”

“…From these simulations, the drug water -membrane distribution coefficient log D (derived using Eq. 2), can be compared with experimental counterparts, as we have done previously (34). Moreover, drug-membrane interactions are crucial for understanding drug pharmacological properties, as cell membrane localization and permeation rates mediate the mechanism by which a drug affects its targets (34).…”