Table 3.

Structural features of the CYP3A4-inhibitor complexes

compound	Fe-N bond		pyridine ring rotation (°)b	I-helix displacement (Å) c	H-bond with Ser119 (Å) d	pyridine-R2 ring angle and overlap	Phe304-R1 ring angle (°)and overlap	Boc-group conformation and contacts
	distance (Å)	angle (°)a
pyridyl-methyl linker
4a (S, R)	2.38	10	17	0.67–0.81	3.10	−25°; partiale	90°; nonee	traceable; 106, 108, 215, 374
4b (R, S)	2.26	3	25	1.39–0.88	2.54	20°; half	0°; half	traceable; 57, 108, 220
4c (R, R)	2.21	5	20	1.36–1.15	2.63	15°; half	0°; half	traceable; 108, 220, 482
4d (S, S)	2.25	3	28	0.95–1.06	2.55	15°; half	15°; full	traceable; 108, 220
6a (S, S)	2.40	0	30	0.79–1.24	2.87	32°; half	12°; full	traceable; 108, 220
pyridyl-ethyl linker
4e (S, R)	2.22	5	47	2.16–2.36	3.16	− 70°; partial	87°; none	traceable; 108, 481
4f (R, S)	2.29	2	20	1.25–0.85	3.24	− 35°; half	68°; none	disordered
4g (R, R)	2.25	5	33	0.97–1.37	2.93	−45°; half	25°; full	traceable, 105–108, 120
4h (S, S)	2.31	5	20	0.54–0.71	2.99	− 23°; half	10°; half	traceable; 108, 220
6b (S, S)	2.25	5	25	0.88–0.86	3.04	−40°; half	30°; half	disordered
Ritonavirf (R, R)	2.16	8	45g	1.99–2.18	2.92 (O24)	−65°; none g	53°; half
					2.84 (O41)
					3.01 (N11)

^{a –}Deviation from perpendicularity.

^{b –}Angle between the planes passing through the pyridine ring and the NB-ND heme atoms

^{c –}Distance between the C_α-atoms of Phe304 and Ala305 in the inhibitor-bound and ligand-free CYP3A4 (PDB ID 5VCC).

^{d –}Hydrogen bond length between the inhibitor O21 atom and Ser119:OG. Ritonavir’s atoms H-bonded to Ser119 (5VC0 structure) are indicated in brackets.

^{e –}In 4a, R₁ and R₂ side groups are placed near the heme-ligating pyridine and Phe304, respectively

^{f –}Parameters derived from the 5VC0 structure. Side-group stereochemistry if the backbone hydroxyl group was removed.

^{g –}Respective angle and overlap for the thiazole ring.