Abstract
Drug isomers may differ in their proarrhythmia risk. An interesting example is the drug sotalol, an antiarrhythmic drug comprising d- and l- enantiomers that both block the hERG cardiac potassium channel and confer differing degrees of proarrhythmic risk. We developed a multi-scale in silico pipeline focusing on hERG channel – drug interactions and used it to probe and predict the mechanisms of pro-arrhythmia risks of the two enantiomers of sotalol. Molecular dynamics (MD) simulations predicted comparable hERG channel binding affinities for d- and l-sotalol, which were validated with electrophysiology experiments. MD derived thermodynamic and kinetic parameters were used to build multi-scale functional computational models of cardiac electrophysiology at the cell and tissue scales. Functional models were used to predict inactivated state binding affinities to recapitulate electrocardiogram (ECG) QT interval prolongation observed in clinical data. Our study demonstrates how modeling and simulation can be applied to predict drug effects from the atom to the rhythm for dl-sotalol and also increased proarrhythmia proclivity of d- vs. l-sotalol when accounting for stereospecific beta-adrenergic receptor blocking.
| Original language | English |
|---|---|
| Pages (from-to) | 163-177 |
| Number of pages | 15 |
| Journal | Journal of Molecular and Cellular Cardiology |
| Volume | 158 |
| DOIs | |
| State | Published - Sep 2021 |
| Externally published | Yes |
Funding
The work in C.E.C. I.V. H.W. J.T.S. V.Y.Y. and S.Y.N. groups were supported by NIH NHLBI grants 5R01HL128537, 2R01HL128537, 5U01HL126273, NIH Common Fund 1OT2OD026580-01 and 3OT2OD026580-01 (C.E.C. and I.V.). Support was also provided by the following: American Heart Association Predoctoral Fellowship16PRE27260295 (K.R.D.) and Career Development Award 19CDA34770101 (I.V.), NIH NHLBI grants 1R01HL152681 (C.E.C. and I.V.) and R01HL128537 (S.Y.N.), Canadian Institutes of Health Research Project Program grant Funding Reference Number 156236 (S.Y.N.), Department of Physiology and Membrane Biology Research Partnership Fund (I.V. and C.E.C.), Extreme Science and Engineering Discovery Environment (XSEDE) Grant MCB170095 (I.V. C.E.C. K.R.D.), National Center for Supercomputing Applications (NCSA) Blue Waters Broadening Participation Allocation (C.E.C. I.V. K.R.D.), Texas Advanced Computing Center (TACC) Leadership Resource AllocationMCB20010 (I.V. C.E.C. K.R.D.), Oracle cloud for research allocation (I.V. C.E.C.), Pittsburgh Supercomputing Center (PSC) Anton 2 allocationsPSCA17085P, PSCA16108P, PSCA18077P, MCB160089P, and PSCA17021P (I.V. C.E.C. K.R.D. S.Y.N.). Anton 2 computer time was provided by the PSC through Grant R01GM116961 from the National Institutes of Health. The Anton 2 machine at PSC was generously made available by D.E. Shaw Research. The work in C.E.C., I.V., H.W., J.T.S., V.Y.Y., and S.Y.N. groups were supported by NIH NHLBI grants 5R01HL128537 , 2R01HL128537 , 5U01HL126273 , NIH Common Fund 1OT2OD026580-01 and 3OT2OD026580-01 (C.E.C. and I.V.). Support was also provided by the following: American Heart Association Predoctoral Fellowship 16PRE27260295 (K.R.D.) and Career Development Award 19CDA34770101 (I.V.), NIH NHLBI grants 1R01HL152681 (C.E.C. and I.V.) and R01HL128537 (S.Y.N.), Canadian Institutes of Health Research Project Program grant Funding Reference Number 156236 (S.Y.N.), Department of Physiology and Membrane Biology Research Partnership Fund (I.V. and C.E.C.), Extreme Science and Engineering Discovery Environment (XSEDE) Grant MCB170095 (I.V., C.E.C., K.R.D.), National Center for Supercomputing Applications (NCSA) Blue Waters Broadening Participation Allocation (C.E.C., I.V., K.R.D.), Texas Advanced Computing Center (TACC) Leadership Resource Allocation MCB20010 (I.V., C.E.C., K.R.D.), Oracle cloud for research allocation (I.V., C.E.C.), Pittsburgh Supercomputing Center (PSC) Anton 2 allocations PSCA17085P , PSCA16108P , PSCA18077P , MCB160089P , and PSCA17021P (I.V., C.E.C., K.R.D., S.Y.N.). Anton 2 computer time was provided by the PSC through Grant R01GM116961 from the National Institutes of Health . The Anton 2 machine at PSC was generously made available by D.E. Shaw Research.
Keywords
- Arrhythmia
- Beta-blocker
- Enantiomer
- Ion channel
- Molecular dynamics
- Stereochemistry
