TABLE 2.
Ligand | Spectral response in CYP46A1 |
Spectral Kd | Cholesterol hydroxylation | Log P | Volume of the ligand/volume of the active site, Å3/Å3 | |
---|---|---|---|---|---|---|
λmax in the absolute spectrum | λmin and λmax in the difference spectrum | |||||
nm | nm | % | ||||
CYP46A1 wild type | ||||||
None | 418 | NA | 100 ± 3a | NA/470b | ||
C3S | 414 | 425, 389 | 7 ± 1 | 5.3c | 431/522 | |
TCP | 427 | 414, 435 | 10 ± 4 | Not detectable | 1.4d | 142/302 |
2-Phenylethylamine | 426 | 414, 435 | 60 ± 7 | Not detectable | 0.9c | ND |
Benzylamine | 425 | 414, 435 | 6,400 ± 80 | 1.1c | ND | |
Aniline | 424 | 413, 432 | 52,000 ± 1,900 | 1.0c | ND | |
Milnacipran | 427 | 413, 435 | 9,500 ± 50 | 86 ± 3 | 1.7c | ND |
THP | 427 | 414, 435 | 60 ± 7 | Not detectable | 2.7c | 278/301 |
VOR | 423 | 412, 431 | 180 ± 10 | 5 ± 1 | 1.0d | 310/450 |
Fluconazole | 425 | 414, 433 | 7,500 ± 50 | 87 ± 4 | 0.4d | ND |
CLO | 422 | 410, 429 | 4 ± 1 | 25 ± 2 | 6.1d | 323/437 |
T306A mutant | ||||||
None | 418 | N/A | ||||
TCP | 424 | 413, 432 | 50 ± 10 | |||
THP | 427 | 415, 435 | 10 ± 3 | |||
VOR | 421.5 | 412, 430 | 280 ± 10 | |||
CLO | 425 | 414, 434 | 5 ± 1 |
a Conditions of the inhibition assay are described under “Experimental Procedures.” The results are the means of three independent experiments ± S.D.
b Calculated as described under “Experimental Procedures.”
c Calculated using Molinspiration.
d Determined experimentally, these data are taken from DrugBank.