TABLE 5.
Nicotine analog free energies of binding to the two human nAChRs compared with free energies of binding (ΔGs) predicted from AChBP crystal structure docking
The number within parentheses is the % increase in ΔG of the analog relative to the ΔG for nicotine; a plus value represents a reduced affinity of the analog for the receptor relative to nicotine.
| Compound | Human Receptor | AChBP | ||
|---|---|---|---|---|
| α7(SH-EP1 Cell) | α4β2 (tsA201 Cell) | Aplysia α7 | Lymnaea | |
| −ΔG (kcal/mol) | Predicted –ΔG (kcal/mol) | |||
| Nic (N) | 8.88 (0%)a | 10.77 (0%)a | 8.88b | 8.88c |
| 1′-MeN | 8.58 (+3%) | 8.66 (+20%) | — | — |
| 1′-EtNorN | 7.99 (+10%) | 8.96 (+17%) | — | — |
| 2′-MeN | 9.72 (−9%) | 10.42 (+3%) | 9.21 | 6.09 |
| 3′-Trans-MeN | 8.70 (+2%) | 8.66 (+20%) | 7.98 | 7.56 |
| 3′-Cis-MeN | 7.56 (+15%) | 7.47 (+31%) | 1.22 | 4.5 |
| 4′-Trans-MeN | 7.34 (+14%) | 10.00 (+7%) | 8.04 | 6.36 |
| 4′-Cis-MeN | 7.79 (+12) | 9.54 (+11%) | 6.3 | 5.01 |
| 5′-Trans-MeN | 8.11 (+9%) | 8.48 (+21%) | 8.37 | 7.16 |
| 5′-Cis-MeN | 6.60 (+26%) | 6.47 (+40%) | 8.33 | 3.66 |
Et, ethyl; Me, methyl; N, nicotine; NorN, nornicotine.
a
%ΔG change relative to ΔG for nicotine.
b
Predicted nicotine −ΔG = 34.1 kcal/mol; normalized to 8.88.
c
Predicted nicotine −ΔG = 37.5 kcal/mol; normalized to 8.88.