Table 1. Binding Free Energy (−ΔG) of Ketamine and Metabolites with GPCRs with Desolvation and Restraint Energies Includeda.
| |
neutral |
protonated |
|||
|---|---|---|---|---|---|
| –ΔG (kcal/mol) | KD (μM) | –ΔG (kcal/mol) | KD (nM) | ||
| S-Ketamine | |||||
| MOR | WT | 7.1 (6.5–7.9) | 7.9 (2.2–20) | 13.9 (12.6–15.2) | 0.096 (0.011–0.83) |
| H297+ | 7.6 (7.3–7.8) | 3.6 (2.4–5.3) | 10.5 (9.8–11.3) | 26 (7.5–89) | |
| KOR | WT | 2.6 (2.6–2.6) | 13 000 (13 000–13 000) | 14.1 (13.5–14.6) | 0.072 (0.029–0.18) |
| H291+ | 4.9 (4.3–5.4) | 310 (130–740) | 8.4 (7.7–9.0) | 910 (310–2700) | |
| R-Ketamine | |||||
| MOR | WT | 7.8 (7.4–8.2) | 2.4 (1.3–4.5) | 12.0 (11.4–12.6) | 2.1 (0.75–5.6) |
| H297+ | 4.6 (3.3–5.8) | 490 (60–4000) | 10.8 (9.9–11.7) | 16 (3.6–72) | |
| KOR | WT | 8.2 (7.9–8.6) | 1.1 (0.59–2.1) | 10.4 (9.2–11.5) | 32 (4.7–220) |
| H291+ | 2.9 (2.9–3.0) | 7500 (7100–8000) | 9.8 (9.1–10.5) | 88 (26–290) | |
| S-Norketamine | |||||
| MOR | WT | 2.7 (2.6–2.9) | 11 000 (8600–13 000) | 13.4 (12.3–14.5) | 0.22 (0.036–1.3) |
| H297+ | 3.8 (3.7–3.9) | 1900 (1600–2200) | 9.6 (8.6–10.6) | 120 (22–640) | |
| KOR | WT | 5.2 (4.8–5.7) | 160 (84–320) | 9.5 (9.1–10.0) | 130 (62–270) |
| H291+ | 6.0 (5.7–6.2) | 49 (32–76) | 6.5 (6.1–6.8) | 21 000 (12 000–37 000) | |
| R-Norketamine | |||||
| MOR | WT | 8.3 (8.1–8.4) | 1.1 (0.84–1.5) | 16.4 (16.1–16.8) | 0.0014 (0.000 81–0.0024) |
| H297+ | 9.2 (9.1–9.3) | 0.22 (0.19–0.25) | 4.4 (3.3–5.5) | 690 000 (110 000–4 100 000) | |
| KOR | WT | 2.0 (0.8–3.2) | 37 000 (5300–250 000) | 19.0 (18.8–19.2) | 0.000 020 (0.000 014–0.000 028) |
| H291+ | 4.9 (4.3–5.5) | 290 (110–740) | 16.5 (15.5–17.6) | 0.0012 (0.000 21–0.0062) | |
| HNK | |||||
| MOR | WT | 3.8 (1.9–5.7) | 1800 (75–45 000) | 11.4 (9.5–12.7) | 5.5 (0.71–140) |
| H297+ | 2.5 (1.7–3.2) | 16 000 (5300–64 000) | 8.3 (7.4–9.2) | 1000 (240–4600) | |
| KOR | WT | 7.4 (7.3–7.5) | 4.5 (4.0–5.1) | 12.8 (11.7–13.9) | 0.57 (0.10–3.6) |
| H291+ | 1.5 (0.6–2.4) | 86 000 (20 000–370 000) | 15.6 (13.9–16.7) | 0.0052 (0.000 84–0.090) | |
a
KD values are calculated as described in Methods from respective ΔG values by FEP MD and correspond to K0 and K1 in equation 2 and . All energies are favorable for binding. Ranges represent minimum and maximum values obtained in both directions of FEP calculation, using interleaved double-wide sampling. WT = without protonation of orthosteric histidine; H291+ and H297+ refer to protonated (+1 charge) histidine (Ballesteros-Weinstein 6.52).