Summary of the sodium channel pore blocker properties examined in this study
| Compound | Clinical Use | % of drug protonated at pH 7 | Mol weight (g/mol) | LogP | # Rotatable bonds | # Hydrogen acceptors | IC50 (µM) | Kinetics, tau on (s) | Kinetics, tau off (s) | Affinity to inactivated Ki | % Pore Occupancy (neutral) | % Pore Occupancy (protonated) | % Pore Occupancy (combined) | Promiscuity (neutral) | Promiscuity (protonated) | Promiscuity (combined) |
| Flecainidea | Antiarrhythmic (1c) | 99.47 | 414.3 | 3.4 | 7 | 4 | 67.63 | 20.04 | 64.97 | 7.9 | 99.89 | 96.98 | 97.00 | 101 | 726 | 722.69 |
| Mexiletinea | Antiarrhythmic (1b) | 99.09 | 179.3 | 2 | 3 | 2 | 230.54 | 8.6 | 12.93 | 26.8 | 7.38 | 88.12 | 87.39 | 593 | 544 | 544.45 |
| Etidocainea | Local anesthetic | 95.06 | 276.4 | 3.8 | 7 | 2 | - | - | - | - | 99.7 | 99.84 | 99.83 | 19 | 229 | 218.63 |
| Bupivacainea | Local anesthetic | 83.58 | 288.4 | 3.9 | 5 | 2 | 67.72 | 7.95 | 16.73 | 5.85 | 100 | 99.62 | 99.68 | 30 | 202 | 173.76 |
| Lamotrigine | Anticonvulsant | 0 | 256.1 | 2 | 1 | 5 | 904.86 | 8.19 | 18.1 | 31.3 | 21.88 | - | 21.88 | 513 | - | 513 |
| Sipatrigine | Anticonvulsant | 91.3 | 372.7 | 3.4 | 2 | 5 | - | - | - | - | 99.42 | - | 99.42 | 196 | - | 196 |
| Lacosamide | Anticonvulsant | 0 | 250.3 | 0.5 | 6 | 3 | - | - | - | - | 63.01 | - | 63.01 | 638 | - | 638 |
| Tolperisone | Muscle relaxant | 96.45 | 245.4 | 3.3 | 4 | 2 | 335.95 | 5.57 | 7.42 | 30.9 | 90.92 | - | 90.92 | 448 | - | 448 |
| Riluzole | ALS treatment | 0.04 | 234.2 | 2.8 | 1 | 4 | 80.98 | 3.9 | 17.6 | 2.17 | 1.03 | - | 1.03 | 316 | - | 316 |
| CORRELATION to % Pore Occupancy (combined) | 0.397 | 0.449 | 0.645 | −0.474 | −0.400 | 0.472 | 0.232 | 0.078 | ||||||||
| CORRELATION to % Pore Occupancy (neutral only) | 0.684 | 0.561 | 0.667 | −0.188 | −0.316 | 0.472 | 0.391 | −0.167 | ||||||||
| CORRELATION to Promiscuity (combined) | 0.009 | −0.609 | 0.219 | 0.111 | 0.201 | 0.720 | 0.635 | 0.339 | ||||||||
| CORRELATION to Promiscuity (neutral only) | −0.632 | −0.874 | −0.390 | 0.044 | 0.604 | −0.433 | −0.546 | 0.807 | ||||||||
| Compound | Clinical Use | % of drug protonated at pH 7 | Mol weight (g/mol) | LogP | # Rotatable bonds | # Hydrogen acceptors | IC50 (µM) | Kinetics, tau on (s) | Kinetics, tau off (s) | Affinity to inactivated Ki | % Pore Occupancy (neutral) | % Pore Occupancy (protonated) | % Pore Occupancy (combined) | Promiscuity (neutral) | Promiscuity (protonated) | Promiscuity (combined) |
| Flecainidea | Antiarrhythmic (1c) | 99.47 | 414.3 | 3.4 | 7 | 4 | 67.63 | 20.04 | 64.97 | 7.9 | 99.89 | 96.98 | 97.00 | 101 | 726 | 722.69 |
| Mexiletinea | Antiarrhythmic (1b) | 99.09 | 179.3 | 2 | 3 | 2 | 230.54 | 8.6 | 12.93 | 26.8 | 7.38 | 88.12 | 87.39 | 593 | 544 | 544.45 |
| Etidocainea | Local anesthetic | 95.06 | 276.4 | 3.8 | 7 | 2 | - | - | - | - | 99.7 | 99.84 | 99.83 | 19 | 229 | 218.63 |
| Bupivacainea | Local anesthetic | 83.58 | 288.4 | 3.9 | 5 | 2 | 67.72 | 7.95 | 16.73 | 5.85 | 100 | 99.62 | 99.68 | 30 | 202 | 173.76 |
| Lamotrigine | Anticonvulsant | 0 | 256.1 | 2 | 1 | 5 | 904.86 | 8.19 | 18.1 | 31.3 | 21.88 | - | 21.88 | 513 | - | 513 |
| Sipatrigine | Anticonvulsant | 91.3 | 372.7 | 3.4 | 2 | 5 | - | - | - | - | 99.42 | - | 99.42 | 196 | - | 196 |
| Lacosamide | Anticonvulsant | 0 | 250.3 | 0.5 | 6 | 3 | - | - | - | - | 63.01 | - | 63.01 | 638 | - | 638 |
| Tolperisone | Muscle relaxant | 96.45 | 245.4 | 3.3 | 4 | 2 | 335.95 | 5.57 | 7.42 | 30.9 | 90.92 | - | 90.92 | 448 | - | 448 |
| Riluzole | ALS treatment | 0.04 | 234.2 | 2.8 | 1 | 4 | 80.98 | 3.9 | 17.6 | 2.17 | 1.03 | - | 1.03 | 316 | - | 316 |
| CORRELATION to % Pore Occupancy (combined) | 0.397 | 0.449 | 0.645 | −0.474 | −0.400 | 0.472 | 0.232 | 0.078 | ||||||||
| CORRELATION to % Pore Occupancy (neutral only) | 0.684 | 0.561 | 0.667 | −0.188 | −0.316 | 0.472 | 0.391 | −0.167 | ||||||||
| CORRELATION to Promiscuity (combined) | 0.009 | −0.609 | 0.219 | 0.111 | 0.201 | 0.720 | 0.635 | 0.339 | ||||||||
| CORRELATION to Promiscuity (neutral only) | −0.632 | −0.874 | −0.390 | 0.044 | 0.604 | −0.433 | −0.546 | 0.807 | ||||||||
All compounds were simulated in the neutral state. Percentage (%) of protonation species were determined using the Major Microspecies Plugin in Marvin Sketch (ChemAxon). Molecular descriptors of drugs were sourced from the rdkit.Chem module. Values for IC50, kinetics and affinity (in italics) were performed using rat Nav1.2 in HEK-293 cells (Lenkey et al., 2010). Percentage (%) pore occupancy values are from Fig. 6 A. Combined % pore occupancy values were calculated by (% Pore Occupancy Neutral * % Neutral Species) + (% Pore Occupancy Protonated * % Protonated Species). The measure for promiscuity was determined by counting the number of 3D FES grid points <10% of the maximum FES value. Combined % promiscuity values were calculated by (% Promiscuity Neutral * % Neutral Species) + (% Promiscuity Protonated * % Protonated Species). Pearson correlation coefficients calculated based on pairwise comparison between each drug property and % pore occupancy (maroon shaded)/promiscuity (green shaded), both neutral and combined values. Potential correlations are highlighted in bold and plotted in Fig. S8.
Denotes compounds for which protonated versions were also simulated.