International Journal of Medicinal Chemistry

Research Article

Studies on 16α-Hydroxylation of Steroid Molecules and Regioselective Binding Mode in Homology-Modeled Cytochrome P450-2C11

Table 2

The inhibitory potency of various steroids on [3H] PROG 16-hydroxylating activity by male rat liver microsomes and their AutoDock results including the binding free energy, the inhibition constant, the distance between C16 carbon atom and feme iron and the angle between C16 carbon atom, C16-hydrogen, and heme Fe iron.


Steroids		[³H]PROG16-hydroxylation (IC₄₀10^-7 M	(kcal/mol)	Inhibition constant	Distance (Å)	Angle ()

No.	Trivial name (°)	[³H]PROG16-hydroxylation (IC₄₀10^-7 M	(kcal/mol)	Inhibition constant	Distance (Å)	Angle ()
(A) 4-Pregnene steroids

(1)	Progesterone	7.55		0.976	5.73	144.8
(2)	3-Hydroxyprogesterone	2.55		—	—	—
(3)	6-Hydroxyprogesterone	10	—	—	—	—
(4)	6-Acetoxyprogesterone	7.40	—	—	—	—
(5)	11-Hydroxyprogesterone	10 M	—	—	—	—
(6)	11-Acetoxyprogesterone	10 M	—	—	—	—
(7)	11-Hydroxyprogesterone	10 M		0.504	5.90	139.3
(8)	16-Hydroxyprogesterone	10 M	—	—	—	—
(9)	16-Methylprogesterone	10 M ^d		4.88	5.32	159.1
(10)	18-Hydroxyprogesterone	10 M	—	—	—	—
(11)	19-Hydroxyprogesterone	10 M	—	—	—	—
(12)	19-Norprogesterone	10 M	—	—	—	—
(13)	20-Hydroxyprogesterone	10 M	—	—	—	—
(14)	21-Hydroxyprogesterone	10 M		1.83	4.73	139.7
(15)	21-Acetoxyprogesterone	10 M	—	—	—	—
(16)	Corticosterone	10 M		1.87	4.75	143.6

(B) 5-Pregnene steroids and cholesterol

(17)	Pregnenolone	1.42		0.532	5.76	139.2
(18)	Pregnenolone-3-acetate	8.00		10.6	4.92	166.8
(19)	Pregnenolone-3-sulfate	1.95	—	—	—	—
(20)	5-Pregnene-3,20-dione	10 M	—	—	—	—
(21)	20-Hydroxypregnenolone	10 M		1.67	5.90	134.8
(22)	21-Hydroxypregnenolone	4.62		1.09	5.95	144.8
(23)	21-Acetoxypregnenolone	6.00		0.114	4.98	136.3
(24)	21-Sulfatepregnenolone	10 M		7.89	4.53	139.7
(25)	5-Pregnen-3-ol	10 M	—	—	—	—
(26)	Cholesterol	10 M		6.65	6.0	159.2

(C) 5-or 5-Pregnane steroids

(27)	5-Pregnan-3,20-dione	7.20		10.6	5.86	149.1
(28)	5-Pregnan-3,20-dione	3.95		2.20	4.93	135.0
(29)	3-Hydroxy-5 -pregnan-20-one	0.62		1.03	5.82	148.9
(30)	3-Acetoxy-5 -pregnan-20-one	4.10	—	—	—	—
(31)	3-Sulfate-5 -pregnan-20-one ^c	10 M	—	—	—	—
(32)	3-Hydroxy-5 -pregnan-20-one	2.25		10.1	5.26	160.9
(33)	3-Hydroxy-5 -pregnan-20-one	0.24		4.03	5.70	150.6
(34)	3-Hydroxy-5 -pregnan-20-one	1.70		1.78	5.59	146.7
(35)	3,11-Dihydroxy-5-pregnan-20-one	1.50	—	—	—	—
(36)	3,16-Dihydroxy-5-pregnan-20-one	11.5	—	—	—	—
(37)	3-Pregnan-3-one	10 M	—	—	—

(D) 4-Androstene steroids

(38)	4-Androsten-3,17-dione	10.0		0.693	5.53	156.1
(39)	4-Androsten-3-one; 17--carboxylaic acid	10	—	—	—	—
(40)	4-Androsten-3-one;17--carboxylaic acid methyl ester	8.01	—	—	—	—
(41)	Testosterone	14.5		4.49	4.34	151.5
(42)	17-Acetoxytestosterone	10 M	—	—	—	—
(E) 5-Androstene steroids

(43)	Dehydroepiandrosterone	6.80	—	—	—	—
(44)	Dehydroepiandrosterone-3-sulfate	10 M		0.0346	4.06	140.9
(45)	5-Androstenediol	6.40		2.88	4.24	160.1

(F) 5- or 5−-Androstane steroids

(46)	5-Androstane	>10 M		7.94	5.90	136.4
(47)	5-Androstane	>10 M		8.26	5.94	149.8
(48)	5-Androstan-3-ol	10.3		4.67	6.0	139.5
(49)	5-Androstan-3-ol	6.5		1.75	4.0	139.2
(50)	5-Androstan-3-ol	5.10		10.8	4.55	145.3
(51)	5-Androstan-3-ol	1.60		5.30	4.49	165.7
(52)	5-Androstan-17-ol	>10 M	—	—	—	—
(53)	5-Androstan-17-ol	3.65		3.20	5.87	150.6
(54)	5-Androstan-3,17-dione	6.50	—	—	—	—
(55)	5-Androstan-3,17-dione	4.80		4.80	5.67	155.2
(56)	3-Hydroxy-5-Androstan-17-one	6.35		7.89	5.51	153.1
(57)	3-Hydroxy-5-Androstan-17-one	4.80		3.34	4.69	160.9
(58)	3-Hydroxy-5-Androstan-17-one	6.50		4.68	5.64	155.4
(59)	3-Hydroxy-5-Androstan-17-one	1.85		2.92	4.12	158.0
(60)	5-Dihydrotestosterone	11.5	—	—	—	—
(61)	5-Dihydrotestosterone	6.00		3.15	5.64	151.1
(62)	5-Androstan-3,17-diol	1.25	—	—	—	—
(63)	5-Androstan-3,17-diol-17-acetate	3.00	—	—	—	—
(64)	5-Androstan-3,17-diol-17-sulfat	10 M		2.51	5.45	145.8
(65)	5-Androstan-3,17-diol	11.1	—	—	—	—
(66)	5-Androstan-3,17 -diol	0.69		2.86	5.82	150.0
(67)	5-Androstan-3-ol-17-carboxylic acid	3.60		0.201	5.0	138.3
(68)	5-Androstan-3-ol-1-carboxylic acid methyl ester	0.43		1.20	5.47	156.0
(69)	5-Androstan-3,17-diol	3.20		1.46	4.14	148.8

(G) Estogens

(70)	Estradiol-17	10 M	—	—	—	—
(71)	Estradiol-17	10 M		7.11	4.15	135.1

C₄₀value was defined as the molar concentration (10^-7 M) of an unlabeled steroid causing 40% inhibition of [³H]PROG16-hydroxylation.
ocking results are not matched with the required parameters (distance = 4–6 Å and angle = 180 ± 45°).
hese imply the mean values of % inhibition C₄₀ value (10^-7 M) obtained from extrapolation, and % increase , respectively, at 10 M of the relevant unlabeled compound.