Quantitative structure-activity relationships (QSARs) in inhibitors of various cytochromes P450: The importance of compound lipophilicity

Figures & data

Table I.  Qsars For P450 Inhibitors Of Cyp1, Cyp2, Cyp3 And Cyp154 Families.

	n	S	R	F
CYP1A1
1. − logIC50 = 0.506 log P + 0.156 a/d^2+1.815 EH+11.810	23	0.3948	0.892	24.74
( ± 0.156) ( ± 0.056) ( ± 1.2353)
CYP1A2
2. − log Ki = 0.875 log D7.4+3.794	16	0.3035	0.982	369.97
( ± 0.046)
3. − log Ki = 0.030 a/d^2 − 0.04 Mr+8.035	16	0.2619	0.912	32.11
( ± 0.019) ( ± 0.001)
4. − log Ki = 0.105 a/d^2 − 0.001 Mr+0.584 l/w + 7.293	18	0.2674	0.916	24.32
( ± 0.022) ( ± 0.00081) ( ± 0.421)
CYP1B1
5. ΔGbind = 0.471 ΔGpart − 6.708	12	0.1612	0.915	51.66
( ± 0.066)
CYP2A6
6. ΔGbind = 0.586 ΔGpart − 2.225	16	0.2476	0.980	334.36
( ± 0.032)
7. ΔGbind = 0.475 ΔGpart − 3.502	5	0.1383	0.997	553.31
( ± 0.020)
CYP2E1
8. − log Ki = 0.932 log P − 0.654 log P^2 − 0.689 HBA − 3.513	12	0.3315	0.854	7.17
( ± 0.231) ( ± 0.174) ( ± 0.163)
9. − log KI = 0.983 log P − 0.203 log P^2 − 1.789	10	0.2177	0.963	89.4
( ± 0.107) ( ± 0.026)
10. logIC50 = 0.113SA − 9.812 QC^L − 2.014 Nc − 0.504	22	0.4428	0.894	23.98
( ± 0.018) ( ± 1.523) ( ± 0.355)
11. − log Ki = 1.047 log D7.4+0.244 − 2.659	11	0.1689	0.968	119.0
( ± 0.096) ( ± 0.024)
CYP3A4
12. ΔGinh = 0.915 ΔGpart − 2.522	6	0.1600	0.989	174.00
( ± 0.069)
13. ΔGbind = 0.926 ΔGpart − 4.990	13	0.3047	0.981	279.73
( ± 0.055)
14. ΔGbind = 0.579 ΔGpart − 3.889	13	0.0873	0.998	304.73
( ± 0.011)
CYP154
15. ΔGbind = 0.707 ΔGpart − 1.854	7	0.1489	0.991	259.41
( ± 0.044)
16. − logMIC = 0.707 log D7.4+1.306	7	0.2952	0.991	259.41
( ± 0.044)

n = number of points; s = standard error; R = correlation coefficient; F = variance ratio

Figure 1 Lipophilicity relationship between − log K_i and log D_7.4 for a series of 16 structurally diverse inhibitors of CYP1A2, shown in Equation (2), Table I.

Figure 2 Lipophilicity relationship between ΔG_bind and ΔG_part for a series of 12 inhibitors of CYP1B1, shown in Equation (5), Table I.

Figure 3 Lipophilicity relationship between ΔG_bind and ΔG_part for a series of 16 inhibitors of CYP2A6, shown in Equation (6), Table I.

Figure 4 Lipophilicity relationship between − log K_i and log D_7.4 for a series of 11 inhibitors of CYP2E1, shown in Equation (11), Table I.

Figure 5 Lipophilicity relationship between ΔG_bind and ΔG_part for a series of 6 statins acting as CYP3A4 inhibitors, shown in Equation (12), Table I.

Figure 6 Lipophilicity relationship between − log MIC and log D_7.4 for a series of 7 inhibitors of the bacterial enzyme, CYP154, shown in Equation (16), Table I. MIC is the minimum concentration giving rise to inhibition of the enzyme.