Mechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targets to which the drug binds, such as an enzyme or receptor. Receptor sites have specific affinities for drugs based on the chemical structure of the drug, as well as the specific action that occurs there.
Drugs that do not bind to receptors produce their corresponding therapeutic effect by simply interacting with chemical or physical properties in the body. Common examples of drugs that work in this way are antacids and laxatives.
In contrast, a mode of action describes functional or anatomical changes, at the cellular level, resulting from the exposure of a living organism to a substance.
Importance
Elucidating the mechanism of action of novel drugs and medications is important for several reasons:- In the case of anti-infective drug development, the information permits anticipation of problems relating to clinical safety. Drugs disrupting the cytoplasmic membrane or electron transport chain, for example, are more likely to cause toxicity problems than those targeting components of the cell wall or 70S ribosome, structures which are absent in human cells.
- By knowing the interaction between a certain site of a drug and a receptor, other drugs can be formulated in a way that replicates this interaction, thus producing the same therapeutic effects. Indeed, this method is used to create new drugs.
- It can help identify which patients are most likely to respond to treatment. Because the breast cancer medication trastuzumab is known to target protein HER2, for example, tumors can be screened for the presence of this molecule to determine whether or not the patient will benefit from trastuzumab therapy.
- It can enable better dosing because the drug's effects on the target pathway can be monitored in the patient. Statin dosage, for example, is usually determined by measuring the patient's blood cholesterol levels.
- It allows drugs to be combined in such a way that the likelihood of drug resistance emerging is reduced. By knowing what cellular structure an anti-infective or anticancer drug acts upon, it is possible to administer a cocktail that inhibits multiple targets simultaneously, thereby reducing the risk that a single mutation in microbial or tumor DNA will lead to drug resistance and treatment failure.
- It may allow other indications for the drug to be identified. Discovery that sildenafil inhibits phosphodiesterase-5 proteins, for example, enabled this drug to be repurposed for pulmonary arterial hypertension treatment, since PDE-5 is expressed in pulmonary hypertensive lungs.
Determination
Microscopy-based methods
Bioactive compounds induce phenotypic changes in target cells, changes that are observable by microscopy and that can give insight into the mechanism of action of the compound.With antibacterial agents, the conversion of target cells to spheroplasts can be an indication that peptidoglycan synthesis is being inhibited, and filamentation of target cells can be an indication that PBP3, FtsZ, or DNA synthesis is being inhibited. Other antibacterial agent-induced changes include ovoid cell formation, pseudomulticellular forms, localized swelling, bulge formation, blebbing, and peptidoglycan thickening. In the case of anticancer agents, bleb formation can be an indication that the compound is disrupting the plasma membrane.
A current limitation of this approach is the time required to manually generate and interpret data, but advances in automated microscopy and image analysis software may help resolve this.