Undecanolactone

Interactions of inhibitor molecules with the human CYP2E1 enzyme active site.[Pubmed:23069620]

Eur J Pharm Sci. 2012 Dec 18;47(5):996-1005.

CYP2E1 is an important enzyme oxidizing ethanol as well as several drugs and other xenobiotics in the human liver. We determined the inhibition potency of structurally diverse compounds against human CYP2E1, and analyzed their interactions with the enzyme active site by molecular docking and 3D-QSAR approaches. The IC(50) values for the tested compounds varied from 1.4 muM for gamma-Undecanolactone to over 46 mM for glycerol. This data set was used to create a comparative molecular field analysis (CoMFA) model. The most important interactions for binding of inhibitors were identified by docking and key features for inhibitors were characterized via the COMFA model. Since the active site of CYP2E1 is flexible, long chain lactones and alkyl alcohols fitted best into the larger open form while the other compounds fitted better in the smaller closed form of the active site. Electrostatic interactions near the Thr(303) residue proved to be important for inhibition of the enzyme activity. Thus, docking analysis and the predictive CoMFA model proved to be efficient tools for revealing interactions between inhibiting compounds and CYP2E1. These approaches can be used to analyze CYP2E1-mediated metabolism and drug interactions in the development of new chemical entities.

Pronounced differences in inhibition potency of lactone and non-lactone compounds for mouse and human coumarin 7-hydroxylases (CYP2A5 and CYP2A6).[Pubmed:10659953]

Xenobiotica. 2000 Jan;30(1):81-92.

1. The structural requirements for a compound to be a potent inhibitor for mouse CYP2A5 and human CYP2A6 enzymes catalysing coumarin 7-hydroxylase activity have been studied. 2. The IC50 of 28 compounds for the pyrazole-treated male DBA/2 mouse and human liver microsomal coumarin 7-hydroxylation were determined at 10 microm coumarin concentration 15 times over Km of coumarin. 3. The three most potent inhibitors for CYP2A5 were gamma-nonanoic lactone, gamma-decanolactone and gamma-phenyl-gamma-butyrolactone with an IC50 = 1.9+/-0.4, 2.1+/-0.2 and 2.4+/-0.3 microM and for CYP2A67-methylcoumarin, butylcyclohexane and indan with an IC50. = 30+/-3.2, 43+/-9 and 50+/-11 microM. 4. Among the 28 compounds studied, only 2-benzoxazolinone, 2-indanone and gamma-valerolactone showed similar inhibitory activity in both species. Indan had a lower IC50 for human than for mouse coumarin 7-hydroxylation, whereas the IC50 of 24 other compounds was higher for human than for mouse coumarin 7-hydroxylation. 5. The largest difference in IC50 between mouse and human activity was observed with 5-substituted phenyl, pentyl, hexyl, heptyl or octyl gamma-lactones or 6-substituted delta-lactones. IC50 of gamma-Undecanolactone and gamma-decanolactone was 500 times lower for mouse than human coumarin 7-hydroxylation. 6. The difference in the IC50 between human and mouse coumarin 7-hydroxylation decreased substantially with the corresponding compounds without the lactone ring. 7. It is concluded that certain 5- or 6-position substituted gamma- and delta-lactones are potent inhibitors for mouse CYP2A5 but not for the orthologous human CYP2A6 and that the active site of CYP2A6 could be smaller than the active site of CYP2A5.