Chapter 1-4 Vocabulary: Small Molecule Drugs

What is a small molecule?

Small molecules are one of several strategies to combat diseases, alongside biologics, cell therapies, gene therapies, and antisense oligonucleotides.
They are typically what people mean by a drug or pill; examples include aspirin and Benadryl.
If you visit a local pharmacy, the vast majority of drugs you could purchase would be categorized as small molecules.
Between 2000-2016, 77\% of all FDA-approved drugs were classified as small molecules.

Many small molecules are found from natural sources.
Taxol is a well-known cancer drug that comes from the bark of the Pacific Yew tree.
Penicillin is another classic example, coming from the Penicillium fungi.
Typically, drugs discovered from natural sources are brought to researchers via anecdotal evidence; researchers then determine the active ingredient, purify it, and test its effect on the treatment of particular diseases.
An alternative source is artificial synthesis: scientists can use mathematical models and computer simulations to predict what kind of chemical might have an effect on treating illnesses. From these predictions, a small molecule can be created in a laboratory from scratch, through multiple steps of chemical reactions.
Whether natural or artificial, the end goal and basic mechanism are similar: small molecule drugs work by interacting with proteins in cells to influence how those proteins function.

The central idea: to use small molecules as tools to influence protein function, and by extension, how cells function.
To understand this, it helps to think of a cell as a factory that manufactures cars (metaphor). Raw materials are transformed into finished goods via machinery.
In cells, machinery is made up of proteins; some proteins transform starting materials into energy, others act like conveyor belts to move cargo within the cell.
There are about 80{,}400 different types of proteins in the human body, each with its own specific function.
The overarching goal is to control how these proteins function, thereby influencing cellular behavior and health.

Aspirin is a widely used small molecule drug, with more than a billion tablets consumed each year.
It is commonly prescribed as a blood thinner and can also reduce pain and inflammation.
Inflammation pathway (simplified): cells manufacture a hormone-like substance called chrysoglandin; cyclooxygenase converts arachidonic acid into prostaglandin, which leads to inflammation.
How aspirin works: it targets the machinery (the protein) that manufactures prostaglandin and inhibits it.
Analogy: cyclooxygenase is like a changing room; arachidonic acid goes in and prostaglandin comes out. If aspirin goes into the changing room and refuses to leave, arachidonic acid cannot be transformed into prostaglandin, so prostaglandin production is blocked and inflammation is reduced.
The inhibition of proteins by small molecules is just one of the many mechanisms of action for small molecule drugs.
The broader aim of pharmaceutical and biotech research is to understand these mechanisms of action, how small molecules interact with proteins, and how the entire system can be leveraged to improve public health.

The transformation from arachidonic acid to prostaglandin via cyclooxygenase can be written as:
\text{arachidonic acid} \xrightarrow{\text{cyclooxygenase}} \text{prostaglandin}
Prostaglandin is a mediator of inflammation; reducing its production helps control inflammatory responses.

Inhibition is one mechanism of action, but it is only one of many possible MOAs for small molecule drugs (e.g., activation, allosteric modulation, covalent modification, etc.).
The goal of current pharmaceutical and biotechnological research is to understand these mechanisms of action, to understand how small molecules interact with proteins, and to leverage that knowledge to improve public health.

Taxol (paclitaxel): a cancer drug derived from the bark of the Pacific Yew tree.
Penicillin: a widely known antibiotic produced by Penicillium fungi.

Given that the majority of approved drugs are small molecules, continued investment in understanding MOAs is crucial for public health.
The balance between natural product discovery and synthetic design reflects broader questions about biodiversity, synthetic accessibility, and access to medicines.
The ability to model and predict chemical interactions with human proteins raises considerations about safety, regulation, and equitable distribution of therapeutics.

Small molecules are a major, historically successful class of therapeutics alongside biologics, cell therapies, gene therapies, and antisense oligonucleotides.
Most drugs in use today are small molecules; many arise from natural sources, but many are also designed and synthesized in the lab.
Their primary mode of action is to interact with proteins, thereby influencing cellular function and health.
Cells can be conceptualized as factories where proteins act as machines that drive metabolism, energy production, and transport.
The human body contains on the order of 80{,}400 distinct protein types, each with specialized functions.
Aspirin exemplifies a small molecule drug: it reduces inflammation by inhibiting cyclooxygenase and thereby lowering prostaglandin production; the classic analogy of a changing room helps visualize enzyme inhibition.
Inhibition is only one of many MOAs for small molecules; ongoing research seeks to map MOAs and translate that knowledge into better health outcomes for populations.