Mechanism of action

In pharmacology, the term mechanism of action (MOA) refers to

the specific biochemical interaction through which a drug substance
produces its pharmacological effect.[2] A mechanism of action
usually includes mention of the specific molecular targets to which
the drug binds, such as an enzyme or receptor.[3] 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.[2] Beta blockers exert their
pharmacological effect, decreased
In contrast, a mode of action (MoA) describes functional or heart rate, by binding to and
anatomical changes, at the cellular level, resulting from the competitively antagonising a type of
exposure of a living organism to a substance. receptor called beta adrenoceptors.[1]

Contents
Importance
Determination
Microscopy-based methods
Direct biochemical methods
Computation inference methods
Omics based methods
Drugs with known MOA
Aspirin
Drugs with unknown MOA
Mode of action
See also
References

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 (peptidoglycan or β-glucans) or 70S ribosome, structures which
are absent in human cells.[4][5]
 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.[6][7]
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.[6]
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.[4][8][9][10]
It may allow other indications for the drug to be identified. Discovery that sildenafil inhibits
phosphodiesterase-5 (PDE-5) proteins, for example, enabled this drug to be repurposed for
pulmonary arterial hypertension treatment, since PDE-5 is expressed in pulmonary
hypertensive lungs.[11][12]

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.[13]

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 Filamentation (top right) can
synthesis is being inhibited. Other antibacterial agent-induced changes indicate that an antibacterial
include ovoid cell formation, pseudomulticellular forms, localized swelling, agent is targeting PBP3,
bulge formation, blebbing, and peptidoglycan thickening.[4] In the case of FtsZ or DNA.[4]
anticancer agents, bleb formation can be an indication that the compound is
disrupting the plasma membrane.[14]

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.[4][13]

Direct biochemical methods

Direct biochemical methods include methods in which a protein or a small molecule, such as a drug
candidate, is labeled and is traced throughout the body.[15] This proves to be the most direct approach to
find target protein that will bind to small targets of interest, such as a basic representation of a drug outline,
in order to identify the pharmacophore of the drug. Due to the physical interactions between the labeled
molecule and a protein, biochemical methods can be used to determine the toxicity, efficacy, and
mechanism of action of the drug.
Computation inference methods

Typically, computation inference methods are primarily used to predict protein targets for small molecule
drugs based on computer based pattern recognition.[15] However, this method could also be used for
finding new targets for existing or newly developed drugs. By identifying the pharmacophore of the drug
molecule, the profiling method of pattern recognition can be carried out where a new target is identified.[15]
This provides an insight at a possible mechanism of action since it is known what certain functional
components of the drug are responsible for when interacting with a certain area on a protein, thus leading to
a therapeutic effect.

Omics based methods

Omics based methods use omics technologies, such as chemoproteomics, reverse genetics and genomics,
transcriptomics, and proteomics, to identify the potential targets of the compound of interest.[16] Reverse
genetics and genomics approaches, for instance, uses genetic perturbation (e.g. CRISPR-Cas9 or siRNA)
in combination with the compound to identify genes whose knockdown or knockout abolishes the
pharmacological effect of the compound. On the other hand, transcriptomics and proteomics profiles of the
compound can be used to compare with profiles of compounds with known targets. Thanks to computation
inference, it is then possible to make hypotheses about the mechanism of action of the compound, which
can subsequently be tested.[16]

Drugs with known MOA

There are many drugs in which the mechanism of action is known. One example is aspirin.

Aspirin

The mechanism of action of aspirin involves irreversible inhibition of the enzyme cyclooxygenase;[17]
therefore suppressing the production of prostaglandins and thromboxanes, thus reducing pain and
inflammation. This mechanism of action is specific to aspirin and is not constant for all nonsteroidal anti-
inflammatory drugs (NSAIDs). Rather, aspirin is the only NSAID that irreversibly inhibits COX-1.[18]

Drugs with unknown MOA

Some drug mechanisms of action are still unknown. However, even though the mechanism of action of a
certain drug is unknown, the drug still functions; it is just unknown or unclear how the drug interacts with
receptors and produces its therapeutic effect.

Acamprosate Meprobamate
Antidepressants Methocarbamol
Armodafinil Paracetamol
Cannabidiol Phenytoin
Cyclobenzaprine PRL-8-53
Demeclocycline Metformin
Fabomotizole Thalidomide
Lithium
Mode of action
In some literature articles, the terms "mechanism of action" and "mode of action" are used interchangeably,
typically referring to the way in which the drug interacts and produces a medical effect. However, in
actuality, a mode of action describes functional or anatomical changes, at the cellular level, resulting from
the exposure of a living organism to a substance.[19] This differs from a mechanism of action since it is a
more specific term that focuses on the interaction between the drug itself and an enzyme or receptor and its
particular form of interaction, whether through inhibition, activation, agonism, or antagonism. Furthermore,
the term "mechanism of action" is the main term that is primarily used in pharmacology, whereas "mode of
action" will more often appear in the field of microbiology or certain aspects of biology.

See also
Mode of action (MoA)
Pharmacodynamics
Chemoproteomics

References
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