title: In silico studies of polyaromatic hydrocarbon inhibitors of cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1.
abstract: A computational study was undertaken to understand the nature of binding and the structural features that play a significant role in the binding of arylacetylene molecules to cytochrome P450 enzymes 1A1, 1A2, 2A6, and 2B1. Nine polycyclic arylacetylenes determined to be mechanism-based P450 enzyme inhibitors were studied. The lack of polar substituents in these compounds causes them to be incapable of hydrogen bonding to the polar protein residues. The four P450 enzymes of interest all have phenylalanine residues in the binding pocket for potential pi-pi interactions with the aromatic rings of the inhibitors. The inhibition potency of these arylacetylenes toward P450s 1A1 and 2B1 showed a dependence on the proximity of the inhibitor's triple bond to the prosthetic heme Fe of the enzyme. In P450 enzyme 1A2, the inhibitor's potency showed more dependence on the pi-pi interactions of the inhibitor's ring systems with the phenylalanine residues of the protein, with the proximity of the inhibitor triple bond to the heme Fe weighing in as the second most important factor. The results suggest that maximizing the pi-pi interactions with phenylalanine residues in the binding pocket and optimum proximity of the acetylene moiety to the heme Fe will provide for a substantial increase in the potency of the polyaromatic hydrocarbon mechanism-based inhibitors. A fine balance of these two aspects of binding coupled with attention to supplementing hydrophobic interactions could address potency and selectivity issues for these inhibitors.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana, One Drexel Drive, New Orleans, Louisiana 70125, USA.
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: Ping
authors.initials: P
authors.lastname: Jin
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
authors.forename: Cheryl L Klein
authors.initials: CL
authors.lastname: Stevens
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D051381:Rats
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D011084:Polycyclic Aromatic Hydrocarbons; D003577:Cytochrome P-450 Enzyme System