Table 1.

Summary of AF drugs, ionic targets, and related computational work.

Drug	Class	Target	Computational work
Flecainide	Ic	INa (Roden and Woosley, 1986) Ito, IKur, IKr (Tamargo et al., 2004)	Functional:
			- Flecainide and lidocaine state specific binding models incorporating detailed voltage- and pH-dependence (Moreno et al., 2011)
			Structural:
			Gómez et al. (2014) and Melgari et al. (2015)
Propafenone	Ic	INa, Ito, IK1, IK (Duan et al., 1993) Ito, IKur, IKr, IKs (Tamargo et al., 2004) IK,2P (Schmidt et al., 2013)	Functional:
			- State-specificity and kinetics of binding via genetic algorithm search (Pásek and Simurda, 2004)
			Structural:
			Gómez et al. (2014) and Ngo et al. (2016)
Amiodarone	III	IKr, IKs, Ito, IKur (Tamargo et al., 2004) INa, ICa (Nattel et al., 1992) IK,2P (Gierten et al., 2010)	Functional:
			- Multi-target modeling of drug action in AF via Hill-type conductance-only block (Loewe et al., 2014)
			- Pharmacodynamic modeling of drug–drug interactions (Chen et al., 2015)
			- Effect of pharmacologically altered INa kinetics on post-repolarization refractoriness and APD prolongation (Franz et al., 2014)
			- Mechanistic understanding of amiodarone effects in 1D and 3D, focus on QT prolongation (Wilhelms et al., 2012)
			- Amiodarone targeting INaL in failing human myocardium simulations (Maltsev et al., 2001)
			Structural:
			Zhang et al. (2016)
Dronedarone	III	IKr, IKs, IK1, INa, ICaL (Gautier et al., 2003) IKr, IKs (Tamargo et al., 2004)	Functional:
			- Frequency and concentration dependent effects in cAF remodeled hearts (Loewe et al., 2014)
			- Drug–drug interaction dronedarone (Denisov et al., 2018)
Ibutilide	III	IKr (Tamargo et al., 2004)	Functional:
			- Clinical intervention with ibutilide linked with simulated phase synchrony between tissue regions (Vidmar et al., 2015)
Vernakalant	III	Ito, IKr, IKur, IK,ACh, INa (Fedida, 2007) IK,2P (Seyler et al., 2014)	Functional:
			- Multi-target, cellular mode of action (Loewe et al., 2015)
			- AF termination simulated by INa block with rapid dissociation through decreased wavebreak and blocked rotor generation (Comtois et al., 2008)
			Structural:
			Eldstrom and Fedida (2009)
Dofetilide	III	IKr (Tamargo et al., 2004)	Functional:
			- Multiscale cardiac toxicity (TdP risk) predictor (Costabal et al., 2018)
			- Contribution of fibroblasts to cardiac safety pharmacology (Gao et al., 2017)
			- Interaction of hERG channel kinetics and putative inhibition schemes in long QT syndrome (Romero et al., 2014)
			- New hERG Markov model including drug-binding dynamics for early drug safety assessment (Di Veroli et al., 2012)
			- Gender and age on dofetilide induced QT prolongation (Gonzalez et al., 2010)
			Structural:
			Dux-Santoy et al. (2011), Saiz et al. (2011) and Varkevisser et al. (2013)
Sotalol	III	IKr (Kpaeyeh and Wharton, 2016) IK (Carmeliet, 1985)	Functional:
			- Prediction of drug effects at therapeutic doses in controlled clinical trials and real-life conditions (Chain et al., 2013)
			- Identifying total area of the ECG T-wave as a biomarker for drug toxicity (Jie et al., 2010)
			Structural:
			DeMarco et al. (2018)
Ranolazine	I, anti-anginal drug	INaL, late ICa, peak ICa, INCX, IKr, IKs (Antzelevitch et al., 2004)	Functional:
			- Antiarrhythmic drug effect specifically in inherited long-QT syndrome and heart failure-induced remodeling (Moreno et al., 2013)
			- Prevention of late phase-3 EADs (Morotti et al., 2016)
			- Combined antiarrhythmic and torsadogenic effect of INaL and IKr block on hV-CMs (Trenor et al., 2013)
			Structural:
			Du et al. (2014)
Cardiac glycosides (digitalis compounds)	V	NKA (Vivo et al., 2008; Schmidt et al., 2018) Vagal stimulation (Falk, 1991)	Functional:
			- Effect NKA on cell and tissue refractoriness and rotor dynamics (Sánchez et al., 2012)
			- Physiologically based PK model (Neuhoff et al., 2013)
			- Two compartment PK-PD model for clinical dosage effect (Jelliffe et al., 2014)
			Structural:
Weiss (2007)