Table 4

Theoretical prediction of the product distribution taking both electronic (A) and orientation (B) factors into account

orthometaparaRest of Molecule
A. HOMO electron densities
DFT0.200.060.411.33
HF0.200.080.491.23
B. Average distances
Atorvastatin
d(OHeme,CSub) (Å)4.1  ± 0.33.4  ± 0.24.3  ± 0.4
V max(pmol · mg−1 · min−1)5,376  ± 4095,463  ± 169
Atorvastatin lactone
d(OHeme,CSub) (Å)4.7  ± 0.23.4  ± 0.23.5  ± 0.3
V max(pmol · mg−1 · min−1)4,235  ± 20514,312  ± 348

Part A of the table shows the computed HOMO electron densities at the aromatic carbon atoms of acetanilide (R = NHCOCH3). Carbon positions are given relative to the substituent R. The table shows the results of two quantum mechanical approaches: Hartree-Fock (HF) and density functional theory (DFT). Part B shows the calculated average distances between the heme oxygen atom and the nearest aromatic carbon atoms of the substrate,d(OHeme,CSub). Experimental rate constants for isolated CYP3A, Vmax (see Table 1), are given to facilitate comparison. The computed distances are averages of 50 snapshots. Values are presented as means ± SD.