In vitro effects and in silico analysis of newly synthetized pyrrole derivatives on the activity of different isoforms of Cytochrome P450: CYP1A2, CYP2D6 and CYP3A4

Four pyrrole based hydazide-hydrazones with established low hepatotoxicity and promising antiproliferative activity were evaluated (at 1µM concentration) for possible inhibitory activity on human isoforms of Cytochrome P450 CYP1A2, CYP3A4 and CYP2D6. The compounds didn't exert any statistically significant inhibitory effects on CYP1A2 and CYP2D6. However on CYP3A4 only 12 resulted in low statistically significant inhibitory effect decreasing the enzyme activity by 20%, compared to the control (pure CYP3A4). In addition the potential interactions of 12 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. The most active CYP3A4 inhibitor 12 demonstrated good binding affinity and was in close vicinity to the het Fe ion (2.88 Å). Overall, good correlation between the in vitro results and the free binding MM/GBSA recalculations were observed