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.

Figure 1

3D structures of P450s 1A1 (A) and 2B1 (B) obtained from homology modeling. The protein is shown as a ribbon model and the Heme residue is depicted as stick model.

Figure 2

Structures of arylacetylene inhibitors used for the study

Figure 3

Depicts binding pockets of P450 enzymes 1A1 (A), 1A2 (B), 2A6 (C) and 2B1 (D) with heme and Phenylalanine residues as stick models showing Gaussian contact molecular surfaces in green dots.

Figure 4

Illustrates the π–π interactions between the protein and the ligand and the proximity of the triple bond to the heme Fe atom for the representative molecule 1EP docked in the binding pockets of P45 enzymes 1A1 (A), 1A2 (B) and 2B1 (C). The residues and inhibitor are shown as stick models.

Figure 5

(A), (B), and (C) Relationship between the inhibitor concentration and Heme-C distance for P450 enzymes 1A1, 1A2 and 2B1; (D), (E), and (F) Relationship between the inhibitor concentration and distance between centroids of aromatic rings of Phenylalanine residues and inhibitor for P450 enzymes 1A1, 1A2 and 2B1.

Figure 6

(A) Represents binding modes of most potent inhibitors 1MEP and 2EPHEN for P450 enzyme 1A1; (B) represents binding modes of most potent inhibitor 1MEP for P450 enzyme 1A2. All interacting residues and the inhibitors are shown as stick models.