Table 2.
High-Spin Fraction, Dissociation Constant Kd, and Binding Free Energy ΔGb° of Palmitic Acid and Various Drug Molecules in PM P450BM3
| Substrate | % High spin | Kd (μM) |
ΔGb° (kcal/mol) |
|
|---|---|---|---|---|
| Experimental | Theoretical | |||
| Palmitic acid | 94 ± 10 | 1.3 ± 0.9 | −8.1 ± 0.4 | ND |
| Diclofenac | 83 ± 4 | 64.9 ± 3.9 | −5.7 ± 0.1 | −4.95 ± 0.62 |
| Naproxen | 80 ± 2 | 4.6 ± 2.9 | −7.4 ± 0.4 | −15.20 ± 0.77 |
| S-warfarin | 75 ± 3 | 0.7 ± 0.4 | −8.4 ± 0.3 | −11.44 ± 0.68 |
| R-warfarin | −1.84 ± 0.68 | |||
| Lovastatin | 77 ± 3 | 3.3 ± 1.5 | −7.5 ± 0.3 | −6.15 ± 0.78 |
| Dextromethorphan | 74 ± 5 | 3.7 ± 1.2 | −7.4 ± 0.2 | −6.89 ± 0.64 |
| MDMA | ND | ND | ND | −6.76 ± 0.57a |
| −6.21 ± 0.42b | ||||
| Astemizole | ND | ND | ND | −10.68 ± 0.91a |
| −8.57 ± 0.88b | ||||
| −3.17 ± 0.53c | ||||
| Nicotined | ND | 23.5 ± 6.3 | −6.3 ± 0.2 | −4.60 ± 0.66e |
| Cotinined | ND | 415 ± 11 | −4.6 ± 0.1 | −7.07 ± 0.60 e |
| Metyraponed | ND | 3.6 ± 0.6 | −7.4 ± 0.1 | −9.09 ± 0.41 |
ND, no data.
a
Positioned for N-dealkylation.
b
Positioned for O-dealkylation.
c
Positioned for C-H hydroxylation.
d
Type II binding mode.
e
Calculated using productive binding mode.