Drugs entering the body will be catalyzed into polar molecules under the action of a series of enzymes, and the process of exerting drug efficacy or being excluded from the universe by the normal metabolic system is drug metabolism, which is a self-protection method of the body. Drug metabolism has become an important part of pharmacological research. Studying the metabolic process and chemical changes of drugs in the body is of great significance for the elaboration of pharmacological effects, toxicity studies, structural modification, etc. The most important role in the process of drug metabolism is the various enzymes involved, including cytochromes. Enzymes P450, reductase, peroxidase, monooxygenase and hydrolase. Cytochrome CYP450 inhibition analysis is an important part of the drug discovery process, as adverse interactions between drugs will lead to the termination of a drug development program, withdrawal of a drug from the market, or limited therapeutic use. In vitro ADME assays also need to be performed early due to the need to weed out underperforming drug candidates early in the drug discovery process. Today we will discuss the various isoforms of cytochrome P450 and the application of computer methods in predicting drugs.
Cytochrome P450
Cytochrome P450 (cytochrome P450 enzyme system, CYP450) mainly exists in the endoplasmic reticulum of the liver and other tissues. It is a type of hemoglobin-coupled monooxygenase. Its function requires the participation of coenzyme NADPH and molecular oxygen. It is mainly involved in oxidation reactions in the biotransformation of drugs, including loss of electrons, dehydrogenation reactions and oxidation reactions. CYP450 is the main drug metabolizing enzyme system.
CPY450 introduces oxygen into drug molecules by activating molecular oxygen so that one of the oxygens binds to organic molecules while reducing the other oxygen atom to water. The types of reactions catalyzed by CYP450 include the oxidation of alkanes and aromatic compounds; the epoxidation of alkenes, polynuclear aromatics and halogenated benzene; the dealkylation of secondary amines, tertiary amines and ethers; the deamination of amines; Converted to N-oxide, hydroxylamine and nitroso compounds and dehalogenation of halogenated hydrocarbons, etc.
CYP450 is a general term for a group of enzymes, consisting of many isozymes and subtypes. When naming, CPY is used to represent CYP450, followed by Arabic numerals to indicate family members of CPY450, such as CYP1, CPY2, CPY3, etc., and letters are added after the numbers, It represents subfamilies, such as CYP1A, CYP2C, CYP2D, CYP2E, etc. CPY450 was first discovered in the 1960s. At least 57 CPY genes have been reported, which are divided into 18 families and 43 subfamilies. Although there are multiple CPY450 isoforms in liver microsomes, only a few enzymes are involved in drug metabolism, of which CPY3A4 is the most involved.
Among them, the content of CYP3A4 accounts for 70% of the total amount of CPY in the intestine and 30% of the total amount of CYP in the liver. Inhibiting CPY3A4 will lead to an increase in the concentration of drugs in the blood and may cause toxic side effects. Activating CPY3A4 will enhance its effect on drugs. Metabolism may reduce the efficacy of the drug. Studies have shown that some drugs are substrates of CPY3A4 and P-glycoprotein (P-gp), and some drugs enter intestinal epithelial cells through passive transport, which will be metabolized by CYP3A4 and effluxed by P-gp. To the intestinal lumen, the drug forms a continuous and repeated cycle between the intestinal cell nuclei and the intestinal lumen, resulting in reduced drug absorption and limiting the amount of drug entering the circulatory system. Many opioid analgesics are metabolized by CYP3A4 and are simultaneously substrates, inhibitors, or inducers of P-gp. DDI mediated by P-gp and CYP3A4 commonly occurs with concomitant use of antiretroviral drugs. The plasma concentration of methadone is significantly reduced by ritonavir, because ritonavir induces CYP3A4 to increase the metabolism of methadone, while inhibiting its efflux by P-gp.
Computer Prediction Methods for Drug Metabolism
Using computer models to predict the possible metabolism of drugs in the early stage of drug discovery will greatly save the cost of drug development and improve the success rate of drug discovery. Includes prediction of CPY450 substrates, inhibitors, metabolic sites and metabolites.
Summarize
Due to the importance of this topic for drug discovery, the momentum of metabolic prediction software is expected to continue for the foreseeable future, but a lack of high-quality data will inevitably hinder its progress, while there is room for further improvements in the accuracy of the algorithms. Currently, the focus has been on CYP metabolism since CYP metabolism is closely related to phase I drug metabolism, but other enzymes involved in clearance pathways also require more attention, such as glutathione transferase and sulfotransferase Wait.
References
Tyzack J D, Kirchmair J. Computational methods and tools to predict cytochrome P450 metabolism for drug discovery[J]. Chemical biology & drug design, 2019, 93(4): 377-386.