Modeling of interactions between xenobiotics and cytochrome P450 (CYP) enzymes

摘要: The adverse effects to humans and environment of only few chemicals are well known. Absorption, distribution, metabolism excretion (ADME) the steps pharmaco/toxicokinetics that determine internal dose which organism is exposed. Of all xenobiotic-metabolizing enzymes, cytochrome P450 (CYP) enzymes most important due their abundance versatility. Reactions catalyzed by CYPs usually turn xenobiotics harmless excretable metabolites, but sometimes an innocuous xenobiotic transformed into a toxic metabolite. Data on ADME toxicity (ADMET) properties compounds increasingly generated using in vitro modeling (in silico) tools. Both physics-based empirical approaches used. Numerous ligand-based target-based as combined methods have been employed evaluate determinants CYP ligand binding predicting sites inhibition characteristics test molecules. In silico prediction CYP-ligand interactions made crucial contributions understanding 1) recognition affinity; 2) likely metabolites from substrates; 3) inhibitors potency. Truly predictive models outcomes cannot be created without incorporating metabolic characteristics; help producing such information filling gaps experimentally derived data. Currently not mature enough replace standard vivo approaches, they already used component risk assessment drugs other chemicals.