title: Structural requirements for inhibitors of cytochromes P450 2B: assessment of the enzyme interaction with diamondoids.
abstract: The series of diamondoids: adamantane, diamantane, triamantane, 2-isopropenyl-2-methyladamantane and 3-isopropenyl-3-methyldiamantane (3-IPMDIA), were employed to elucidate the molecular basis of their interaction with the active site of cytochromes P450 (CYP) of a 2B subfamily. These potent inhibitors of CYP2B enzymes were docked into the homology model of CYP2B4. Apparent dissociation constants calculated for the complexes of CYP2B4 with docked diamandoids agreed closely with the experimental data showing inhibition potency of the compounds and their binding affinity to CYP2B4. Superimposed structures of docked diamondoids mapped binding site residues. As they are mainly non-polar residues, the hydrophobicity plays the major role in the binding of diamondoids. Overlapping structure of diamondoids defined an elliptical binding cavity (5.9A inner diameter, 7.9A length) forming an angle of approximately 43 degrees with the heme plane. CYP2B specific diamondoids, namely 3-IPMDIA, showing the highest binding affinity, should be considered for a potential clinical use.
authors.affiliation: Department of Biochemistry, Faculty of Science, Charles University, Hlavova 2030, Prague 2 CZ-12840, Czech Republic. hodek@natur.cuni.cz
authors.forename: Petr
authors.initials: P
authors.lastname: Hodek
authors.forename: Lucie
authors.initials: L
authors.lastname: Bortek-Dohalská
authors.forename: Bruno
authors.initials: B
authors.lastname: Sopko
authors.forename: Miroslav
authors.initials: M
authors.lastname: Sulc
authors.forename: Stanislav
authors.initials: S
authors.lastname: Smrcek
authors.forename: Jirí
authors.initials: J
authors.lastname: Hudecek
authors.forename: Josef
authors.initials: J
authors.lastname: Janků
authors.forename: Marie
authors.initials: M
authors.lastname: Stiborová
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D019362:Cytochrome P-450 CYP2B1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D015394:Molecular Structure; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar
chemical_list: C461381:2-isopropenyl-2-methyladamantane; C461382:3-isopropenyl-3-methyldiamantane; D004791:Enzyme Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; D019362:Cytochrome P-450 CYP2B1; D000072467:Cytochrome P450 Family 2; C465241:cytochrome P-450 CYP2B4 (rabbit); D000218:Adamantane