Quercetin targets cytochrome P450 enzyme (CYP1A2) in colorectal cancer.

Dietary and environmental factors significantly impact the development of colorectal cancer (CRC), especially when procarcinogens are metabolized by cytochrome P450 enzymes. Heterocyclic amines and other xenobiotics linked to CRC are bioactivated by cytochrome P450 1A2. Quercetin is a naturally occurring dietary flavonoid that inhibits CYP1A2 activity, which has been identified as a potential target and shown to have chemopreventive and anticancer effects. However, little is understood about the molecular signals underlying the interaction between quercetin and CYP1A2. In this work, quantum theory, including DFT and NCI-RDG analysis, was used to investigate the binding mechanism and stability of quercetin within the active site of CYP1A2, followed by docking and MD (molecular dynamics) simulations. The theoretical analysis depicted the chemical reactivity and other properties of quercetin. The docking study results indicate that quercetin forms π-π interactions and hydrogen bonds with key residues of the catalytic site in the vicinity of the heme region of CYP1A2. High inhibitory activity is indicated by high binding affinity. After the MD simulation, quercetin-CYP1A2 complexes showed less variation in backbone and ligand structures, exhibited strong intermolecular interactions, and remained stable over the simulation timescale, representing a dynamically stable binding process. Blocking the catalytic site of CYP1A2 with quercetin, restricting access of the substrate to iron within the heme, was speculated to decrease the metabolic transformation of dietary procarcinogens and their association with colon cancer by the metabolic activation process of CYP1A2, as indicated by the results. Although the study indicated the valuable role of quercetin as a regulator of CYP1A2 metabolism, experimental evidence remains important to support the biological efficacy of quercetin in the prevention of CRC.