Review of Ligand Specificity Factors for CYP1A Subfamily Enzymes from Molecular Modeling Studies Reported to-Date

Abstract

The cytochrome P450 (CYP) family 1A enzymes, CYP1A1 and CYP1A2, are two of the most important enzymes implicated in the metabolism of endogenous and exogenous compounds through oxidation. These enzymes are also known to metabolize environmental procarcinogens into carcinogenic species, leading to the advent of several types of cancer. The development of selective inhibitors for these P450 enzymes, mitigating procarcinogenic oxidative effects, has been the focus of many studies in recent years. CYP1A1 is mainly found in extrahepatic tissues while CYP1A2 is the major CYP enzyme in human liver. Many molecules have been found to be metabolized by both of these enzymes, with varying rates and/or positions of oxidation. A complete understanding of the factors that govern the specificity and potency for the two CYP 1A enzymes is critical to the development of effective inhibitors. Computational molecular modeling tools have been used by several research groups to decipher the specificity and potency factors of the CYP1A1 and CYP1A2 substrates. In this review, we perform a thorough analysis of the computational studies that are ligand-based and protein-ligand complex-based to catalog the various factors that govern the specificity/potency toward these two enzymes.

Keywords: P450 1A1; P450 1A2; active site; cytochrome; docking; dynamics; molecular modeling; quantitative structure activity studies (QSAR).

Figure 1

(A) The X-ray crystal structures of CYP1A1 (4I8V.pdb, pink) and CYP1A2 (2HI4.pdb, green) are superposed as ribbon model. Atoms are shown as ball and stick models. Heme is colored white and the substrate flavone is colored yellow. The total rmsd for these structures is 1.4 Å; (B) Native state of the heme bound to Cys sulfur atom as the fifth ligand and the water molecule as the sixth ligand.

Figure 2

The catalytic cycle of oxidation of substrates by CYP enzymes is shown. The heme iron atom is anchored to the enzyme through the entire cycle by its covalent linkage to the sulfur atom of the Cys residue.

Figure 3

The molecular surface representation of the active site pocket of the (A) CYP1A1 and (B) CYP1A2 enzymes colored by lipophilicity where the pink region depicts hydrophilic region of the pocket and the green region depicts the lipophilic region of the pocket. The heme residue is represented as white stick model, the ligand (α-naphthoflavone) is shown as yellow stick model, and the enzyme residues are shown as cyan stick models.

Figure 4

Structures and CYP1A1 & CYP1A2 inhibition data for (A) & (C) linear planar molecules and (B) & (D) triangular planar molecules [(A) and (B) reprinted from reference 34 with permission ].

Figure 4

Structures and CYP1A1 & CYP1A2 inhibition data for (A) & (C) linear planar molecules and (B) & (D) triangular planar molecules [(A) and (B) reprinted from reference 34 with permission ].

Figure 5

Alignment images of group 1 and group 2 inhibitors. (A) and (C) Group 1 represents selective P450 1A1 inhibitors. (B) and (D) Group 2 represents selective P450 1A2 inhibitors. [Figure was reprinted from reference 34 with permission].

Figure 6

Docking studies showing the π-π interactions between the arylacetylenes and the enzymes (A) CYP1A1 and (B) CYP1A2. The docking studies also showed (C) the direct relationship between the inhibitory activity and the heme-acetylene moiety distance for CYP1A1 and (D) the relationship between the inhibitory activity and distance between centroids of aromatic rings of Phe residues and arylacetylenes for CYP1A2. [(A) and (B) reprinted from reference 52 with permission].

Figure 7

Adapted from reference [53] Model of 5-fluoro-2-(3,4,5-trimethoxyphenyl)benzo[d]thiazole (a) and 4-(benzo[d]thiazol-2-yl)benzene-1,2-diol (b) docked into the binding site of CYP1A1. Important residues are shown as sticks.

Figure 8

Adapted from reference [56]. The most favorable binding orientations of 3-NBA docked into the active site of CYP1A1 (A), 1A2 (B) and 1B1 (C). Hydrogen bonds between 3-NBA and the amino acid residues in active site residues are rendered as dashed black lines. 3-NBA (pink), heme (grey) and side chains of important amino acid residues (cyan) are rendered as bold sticks; iron ions as orange spheres.

Figure 9

Structures of compounds studied by Kesharwani et al. [32] and Kahn et al. [57].

Figure 10

Structures of photo-affinity ligands used as binding site probes.