Novel natural inhibitors of CYP1A2 identified by in silico and in vitro screening

Abstract

Inhibition of cytochrome P450 (CYP) is a major cause of herb-drug interactions. The CYP1A2 enzyme plays a major role in the metabolism of drugs in humans. Its broad substrate specificity, as well as its inhibition by a vast array of structurally diverse herbal active ingredients, has indicated the possibility of metabolic herb-drug interactions. Therefore nowadays searching inhibitors for CYP1A2 from herbal medicines are drawing much more attention by biological, chemical and pharmological scientists. In our work, a pharmacophore model as well as the docking technology is proposed to screen inhibitors from herbal ingredients data. Firstly different pharmaphore models were constructed and then validated and modified by 202 herbal ingredients. Secondly the best pharmaphore model was chosen to virtually screen the herbal data (a curated database of 989 herbal compounds). Then the hits (147 herbal compounds) were continued to be filtered by a docking process, and were tested in vitro successively. Finally, five of eighteen candidate compounds (272, 284, 300, 616 and 817) were found to have inhibition of CYP1A2 activity. The model developed in our study is efficient for in silico screening of large herbal databases in the identification of CYP1A2 inhibitors. It will play an important role to prevent the risk of herb-drug interactions at an early stage of the drug development process.

Keywords: CYP1A2; docking; herb–drug interaction; pharmacophore.

Figure 1.

Molecular structure of the template molecules used in this work.

Figure 2.

The molecular structure of selected template by superposing three bifonazole in three different conformations.

Figure 3.

The final pharmacophore of CYP1A2. F1–F3: Aro|Hyd; F4: PiN; F5: Aro|PiN|Hyd|Cat|Acc|Don; V1: Exterior Volume; V2–V8: Excluded Volume.

Figure 4.

Molecular structure of 18 compounds tested in vitro.

Figure 4.

Molecular structure of 18 compounds tested in vitro.

Figure 5.

General workflow used in our study.

Figure 6.

Crystallographic (Red) and docked (Blue) conformations of α-naphthoflavone in the Human Microsomal P450 1A2 receptor site S = −11.1076, rmsd = 0.3061. Note: Hydrogen bond is indicated by the pink dashed line.