Evaluation of the inhibition performance of pyrrole derivatives against CYP450 isoforms

Cytochrome P450 is a heme-containing superfamily accountable for the oxidation of various pharmacologically active drugs. The aim of this study was to conduct in silico and in vitro activity assessments of recently synthesized pyrrole-based compounds against three major CYP450 isoforms – CYP1A2, CYP2D6 and CYP3A4. The in vitro study contained specific cytochrome P450 isoform inhibitors and substrates (for CYP1A2, CYP2D6, and CYP3A4) to determine the inhibition performance of the tile compounds at 1 µM concentration. The in vitro data showed that none of the implemented molecules (MI_a-e and MII_a-e) are capable of inhibiting neither of the CYP isoforms. In addition, the potential interactions of the title compounds and the evaluated CYP isoforms were displayed after molecular docking with Glide (Schrödinger). Induced-fit simulations and binding free energy (MM/GBSA) calculations were applied to elucidate the accessibility in each CYP isoform. None of the pyrrole-based compounds exerted significant inhibition towards the applied isoenzymes. Two of the best scored compounds were visualized in the active site of CYP3A4 (PDB: 2V0M). Overall, good correlation between the in vitro results and the free binding MM/GBSA recalculations was observed.