The role of small-molecule drugs in disease treatment

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Small-molecule drugs have been a mainstay of the pharmaceutical industry for nearly a century and they continue to play a crucial role in the industry’s therapeutic arsenal. Advances in technology and biopharmaceutical research in the last 10 years or so have provided companies with the ability to discover and develop more and more innovative small-molecule therapeutics that hold the ability to treat a range of different indications.

In this article, we explore the field of small-molecule drugs, including what they are, their advantages and disadvantages, and which diseases they can be used to treat.

What are small-molecule drugs?

Small-molecule drugs are defined as any organic compound with low molecular weight, which are discovered, designed, and developed to prompt a specific biological process in the body. Popular examples include antibiotics (such as penicillin), analgesics (such as paracetamol), and synthetic hormones (such as corticosteroids).

According to Bob Discordia, co-founder and chief executive officer (CEO) of recently launched biotech company EQUULUS Therapeutics, which focuses on developing small-molecule drugs for psychiatric and neurological disorders, small-molecule and large-molecule drugs stand as two distinct categories, each with their unique attributes and therapeutic applications. “Small-molecule drugs are by far the more abundant drugs available. They boast the critical ability to swiftly penetrate cell membranes and precisely interact with specific targets within cells.”

There are many ways in which small molecules work to elicit a therapeutic response in the human body. Three of the most common types are:

Enzyme inhibitors: This is where small molecules block enzyme activity to interfere with disease processes;
Receptor agonists/antagonists: Here, small molecules can interact with proteins that exist on the surface of cells to either activate or block the receptor;
Ion channel modulators: This is where small-molecule drugs can modulate the opening and closing of ion channels (proteins embedded in cell membranes that are responsible for regulating the flow of ions into and out of those cells) to treat diseases such as epilepsy.

Many of these mechanisms of action involve a well-defined region on the protein into which a small molecule can fit and bind, known as an “active site.” The geometric arrangement of the amino acids on these active sites means that they only have an affinity for a few naturally occurring molecules within the body. This mechanism is often referred to as the “lock and key” theory; by understanding the requirements of the “lock,” researchers can then create the best “key” – in this case, a small molecule – to fit it and thereby generate a therapeutic response.

Advantages and disadvantages of small-molecule drugs

Small-molecule drugs have many advantages that make them attractive to the biopharma community. They have relatively simple structures and are customizable to meet specific therapeutic goals. They are generally stable and rarely need specialized storage conditions, plus their behavior in vivo is usually predictable, leading to straightforward dosing protocols that patients find easy to manage.

“Small-molecule drugs often have the advantage of oral administration, which makes them more convenient for patients,” explained Jason Tardio, chief operating officer at Ovid Therapeutics. “Because of the cost-effectiveness and convenience associated with these drugs, treatment adherence can be better for small molecules compared with injectable or intravenous drugs. Small-molecule drugs also tend to be more chemically stable and easier to manufacture at scale compared to biologics, for example.”

By altering the atomic composition of small molecules, their overall properties can be fine-tuned to a particular purpose, eliciting only the desired response. The flexibility afforded by being able to explore all “chemical space” in this way means that small-molecule approaches have a significant advantage over other modalities.

Tardio said that small-molecule drugs can also target very specific receptors or enzymes, which means precise therapeutic benefit with fewer off-target effects – in other words, patients will generally experience fewer side effects taking small-molecule medications.

However, it is worth noting that the key disadvantage of conventional small-molecule therapeutics is that they are essentially “one-trick ponies” that can only do one thing, which they keep doing regardless of the physiological state of the patient. This is largely because they are not equipped to receive feedback from the body.

The potential to treat a range of indications

Perhaps one of the best things about small-molecule drugs, however, is their versatility. They can move through the body easily, transferring from the gut via the bloodstream to the site of action, permeating through cell membranes to reach intracellular targets.

“This versatility renders them indispensable across various medical domains, including oncology, cardiovascular health, infectious diseases, and mental health and neurologic disorders,” commented Discordia.

One particular area for which small-molecule drugs are currently being pursued is neurology. According to Discordia, this is because many of these types of drugs have the ability to penetrate the blood-brain barrier, allowing them preferential access to the brain to treat mental health disorders and neurologic conditions. “Large molecules such as proteins and antibodies are essentially unable to penetrate this protective barrier, which exists to shield the brain from toxic substances and eject harmful compounds from the brain into the bloodstream, among other functions,” Discordia continued to explain.

For example, Discordia’s own company, EQUULUS, is developing small-molecule drugs for psychiatric and neurological disorders with a strong focus on addiction disorders. The company’s lead asset, EQL-101, is a psychedelic-inspired anti-addiction therapeutic that is based on the therapeutic benefits of ibogaine. This is a naturally-occurring substance from the Iboga tree that has been used for many years to treat substance use disorders but has a significant and long hallucinogenic phase with dangerous and potentially lethal cardiac side effects. “EQL-101 is non-hallucinogenic and non-cardiotoxic but has been shown in preclinical testing to hold similar efficacy to treat addictions to various substances,” said Discordia.

Furthermore, Tardio’s company, Ovid, is developing a pipeline of small-molecule therapies with novel mechanisms of action that it believes can meaningfully improve the lives of those affected by epilepsies and brain conditions. Its lead asset, OV888, is a ROCK2 inhibitor for the treatment of a rare seizure-related disorder called cerebral cavernous malformation (CCM), while one of its other candidates, OV329, is a GABA-AT inhibitor with potential as an oral treatment for chronic epilepsy and as an intravenous formulation for acute seizures and status epilepticus.

“Small-molecule therapies are often the first-line treatment for seizure-related disorders, primarily because they have been extensively studied and proven to be safe and effective in managing seizures for many patients,” said Tardio. “Small molecules are also more likely to diffuse across the blood-brain barrier and achieve centrally penetrant effects, in comparison to biologic therapies that typically require active, energy-dependent processes for blood-brain penetration (or direct intrathecal delivery) and tend to stimulate self-limiting immunologic clearance mechanisms.”

FDA-approved small-molecule drugs: too many to count

The sheer amount of U.S. Food and Drug Administration (FDA)-approved small-molecule drugs for different indications just goes to show how versatile these types of medications are.

“Over the past 15 to 20 years, a slew of small-molecule drugs have earned acclaim following approval by the FDA, profoundly impacting patient care,” said Discordia. “These include household names such as duloxetine (Cymbalta) for the treatment of depression and anxiety and sildenafil (Viagra) for erectile dysfunction. Moreover, breakthroughs in small-molecule drug development have yielded targeted therapies like desatinib (Sprycel) for chronic myeloid leukemia, as well as apixaban (Eliquis) for atrial fibrillation and anticoagulation.”

In fact, novel small-molecule drug approvals by the FDA increased by more than 50% last year, with 34 new approvals in 2023 compared to 21 in 2022. Small-molecule drugs also represented 62% of total FDA drug approvals in 2023, suggesting that they continue to be crucial in healthcare advancement.

Are we in a golden age of small-molecule drug discovery?

Considering the amount of FDA approvals small-molecule drugs received last year, there is reason to believe we might be in the “golden age” of small-molecule drug discovery. It’s worth noting that one major factor that has contributed to this is the advancement of artificial intelligence (AI).

Traditionally, it takes a lot of time and scientific expertise to discover and synthesize a small molecule that becomes a preclinical candidate. However, AI is now reinventing the processes involved and accelerating drug discovery. It increases speed, lowers cost, improves success rates, and ultimately boosts innovation. In fact, one study found that biotech companies using an AI-first approach have more than 150 small-molecule drugs in discovery and more than 15 already in clinical trials.

Another good example of how AI is helping to revolutionize small-molecule drug discovery is when, last year, the technology helped scientists discover a new antibiotic called abaucin, which can kill Acinetobacter baumannii, a multi-drug resistant superbug that causes fever, chills, and vomiting. Here, AI was able to rapidly screen 7,500 molecules that were found to inhibit A. baumannii, and in one and a half hours, it managed to narrow down 250 potential compounds.

With the help of these advances, the small-molecule drug discovery market size is now estimated to reach $86.65 billion by 2029. It is, therefore, very likely that small-molecule drugs will continue to have a major role to play in treating a range of diseases, just as they have for many years now.