Established Drug Modalities Part 1: Small Molecule Drug Modalities
In modern medicine, drug modalities have evolved from traditional small molecules to cutting-edge modalities such as gene and cell therapies. In a series of articles, we will explore the diverse spectrum of drug modalities, ranging from mature and well-established modalities to emerging biotechnological breakthroughs poised to shape the future of therapeutic interventions and personalized medicine. In this first article, we focus on established drug modalities and overview their properties, advantages, and limitations, as well as the impact they have had in medicine and their prospects for future impact.
Article summary
The initial stages of drug discovery involve dissecting disease mechanisms and pathways to identify potential therapeutic targets. The selection of a drug modality is a strategic decision, considering the advantages and disadvantages in relation to the characteristics of the target and underlying physiological processes.
Small molecule drug modalities, with continuously evolving mechanisms of action and broad range of target classes, remain a cornerstone in modern medicine.
Small molecule drugs have distinct advantages over other modalities, such as the ability to engage targets inside and outside the cell and effectively penetrate various tissues and organs.
Advancements in machine learning and artificial intelligence play an increasingly important role in accelerating small molecule drug discovery and development and improving the efficacy and safety of small molecule drugs.
From Targets to Therapies: Exploring the Spectrum of Drug Modalities in Medicine
The drug discovery and development process often begins with an evaluation of the disease condition to understand the underlying biological processes and mechanisms that lead to its development and progression. Identifying the molecular pathways or genetic factors that trigger or contribute to the disease is often essential for the identification of targets that could be modulated for treatment.
Different disease conditions have different mechanisms and molecular pathways and each pathway may contain multiple potential targets. For example, a disease condition caused by an abnormally high expression level of an enzyme could in principle be modulated via several therapeutic approaches, including inhibiting the enzyme activity via small molecule inhibitors, decreasing the enzyme intracellular levels by decreasing the levels of mRNA via RNA interference approaches.
What is a drug modality? The different types of drugs that can be used to modulate a target and interfere with a disease mechanism or pathway–e.g., small molecules, siRNA, antibodies–are often referred to as drug modalities. Drug modalities can be classified in different groups according to their molecular structure, developmental stage, and clinical application among others.
Once a target is prioritized, having a variety of drug modalities allows to select the most relevant modality that is most likely to be effective at modulating the particular target. Often, multiple modalities can be effective in principle, and the decision to pursue a particular modality often comes down to comparing the advantages and disadvantages of the available modalities to the characteristics of the target and the underlying physiological processes. Extending our example from above, both small molecule inhibitors and small interfering RNA (siRNA) drug modalities can be effective at decreasing enzyme activity, the former by directly binding to the enzyme’s active site and inhibiting activity, while the latter by targeting the enzyme’s mRNA and reducing mRNA levels and subsequently protein levels and enzyme activity. Because most enzymes are intracellular and siRNA molecules typically have poor cell membrane permeability, small molecules are typically the drug modality of choice for blocking enzyme activity.
Depending on their technological maturity and extent of clinical application, therapeutic modalities can be classified within a spectrum – from established to emerging. From this perspective, small molecules, monoclonal antibodies, and proteins and peptides (recombinant and synthetic) can all be classified as established drug modalities.
A Century of Innovation: The Enduring Impact of Small Molecule Drugs in Medicine
Small molecule drugs developed over the last century have had a profound impact on human society by significantly improving health outcomes and transforming medicine. This drug modality has been the main pillar of the pharmaceutical industry, with thousands of small molecule drugs approved by the FDA. While innovation and discovery have contributed to the increasing number of new drug modalities, small molecule drugs continue to dominate, with more than 60 percent of novel drugs approved by the FDA in 2022 being small molecules.
Aspirin, penicillin, retrovir, and lovastatin are only a few small molecule drug examples but illustrate the tremendous impact that this drug modality has had on improving the quality of life and relieving morbidity and mortality for millions of patients.
Acetylsalicylic acid (aspirin) is one of first synthetic small molecule drugs (Figure 1A). It was first synthesized in a stable form by Bayer in 1899. Acetylsalicylic acid is a derivative of salicylic acid, which is naturally occurring in the bark of the willow tree and has been used to relieve pain since ancient times. The primary mechanism of action of aspirin is to inhibit cyclooxygenase, an enzyme involved in the biogenesis of molecules with pro-inflammatory activity. The elucidation of aspirin’s mechanism of action was awarded the Nobel Prize in Physiology or Medicine in 1982.
1928 marks the discovery of penicillin by Alexander Fleming (Figure 1B). Penicillin was the first widely used antibiotic and revolutionized medicine. Its discovery was subsequently awarded the Nobel Prize in Physiology or Medicine in 1945. While initially obtained from mold fermentations, penicillin was first chemically synthesized in the 1940s and administrated in patients as early as 1941. Penicillin exerts its mechanism of action by inhibiting bacterial cell wall synthesis. Specifically, it interferes with the final stages of peptidoglycan synthesis, disrupting the integrity of the bacterial cell wall. Together with salvarsan (discovered by Paul Ehrlich, regarded as the father of modern drug discovery) and prontosil (discovered by Gerhard Domagk and considered to be the first commercially available antibiotic), penicillin marked the beginning of the antibiotic era and despite the emergence of bacterial resistance, penicillin and related analogs are key medicines and still widely used today.
Retrovir, developed by Burroughs Wellcome and introduced in 1987, was the first therapy for human immunodeficiency virus (HIV) infections (Figure 1C). This small molecule drug revolutionized HIV treatment, transforming a life-threatening infection into a manageable chronic condition. Retrovir belongs to the class of nucleoside reverse transcriptase inhibitors and works by interfering with the replication of the virus. Its development and subsequent use underscore the impactful role that small molecule drugs play in combating virus infections. The discovery of retrovir paved the way for the development of numerous antiviral drugs against retroviruses, including protease inhibitors, integrase inhibitors, and combination therapies.
The development of statins, a groundbreaking class of drugs for managing cholesterol levels, traces back to the 1970s. Akira Endo, a Japanese microbiologist, discovered the first statin during a search for antimicrobial agents. With HMG CoA reductase being the rate-limiting enzyme in the cholesterol biosynthesis pathway, the mechanism of action of statins is primarily to inhibit this enzyme. Lovastatin (Figure 1D), the first statin, underwent clinical trials by Merck in the early 1980s. Its effectiveness in lowering the low density lipoprotein (LDL) cholesterol (LDL being causally related to cardiovascular morbidity and mortality) without any major adverse effects led to its regulatory approval by the FDA in 1987. Merck's achievement with lovastatin revolutionized the treatment landscape for disease conditions associated by high LDL cholesterol levels, setting the stage for the development of subsequent statins. Simvastatin (Merck), a lovastatin derivative, gained approval in 1988, followed by pravastatin (Sankyo) in 1991. These statins, along with fluvastatin (Novartis, 1994), atorvastatin (Pfizer, 1996), cerivastatin (Bayer, 1997), and rosuvastatin (Astra Zeneca, 2003), expanded the therapeutic options for patients. Lovastatin's success, together with the blockbuster status of atorvastatin and rosuvastatin, underscored the transformative potential of statins in reducing cardiovascular risk, ushering in a new era in preventive cardiology.
What is a blockbuster drug? A blockbuster drug refers to a drug that generates substantial and sustained commercial success by achieving exceptionally high sales revenue. Specifically, a blockbuster drug is characterized by annual sales exceeding the billion-dollar threshold, often propelled by broad demand and effectiveness in treating prevalent medical conditions. The term is commonly used in the pharmaceutical industry to describe drugs that significantly contribute to the financial success of the pharmaceutical company that develops and markets them.
Figure 1. Examples of small molecule drugs with tremendous impact in medicine. A. Aspirin. B. Penicillin G. C. Retrovir. D. Lovastatin. The structures were generated with RCSB’s chemical sketch tool, available at https://www.rcsb.org/chemical-sketch.
Understanding the Advantages of Small Molecule Drugs in Medicine
Small molecules are low molecular weight organic compounds with relatively simple chemical structures. While conventionally their molecular weight is considered less than 500 Da, small molecule drugs molecular weights have been extending over time above 500 Da. For example, natural products and proteolysis targeting chimeras (PROTACs) often have molecular weights around 1000 Da or higher.
Small molecule drugs have key properties that contribute to their success in medicine. They can typically cross cell membranes effectively, which enables them to reach intracellular targets and is an advantage over many other drug modalities. Small molecule drugs can modulate different types of both intracellular and extracellular biological targets–e.g., enzymes, transcription factors, signaling receptors, and nucleic acids–via diverse mechanisms of action. According to their mechanisms of action, small molecule drugs have traditionally been classified as inhibitors, agonists, and antagonists.
Inhibitors bind to functional sites of their targets, for example, enzymes, and interfere with their activity.
Agonists can bind to their targets, typically cell surface receptors, activating them and leading to a physiological response.
Antagonists bind to their targets and prevent other molecules, for example agonists, from binding to the target; antagonists typically do not have an effect on the activity of their target.
New mechanisms of action are associated with emerging small molecule drug modalities, many of which focus on inducing proximity between a target and an effector molecule, with the latter typically modulating the former. Proximity-based modalities, relatively recent innovations in small molecule drug modalities, exhibit various mechanisms of action, including targeted degradation, targeted stabilization, targeted post-translational modification, and targeted inhibition. For example, molecular glues and PROTACs bring protein targets and E3 ubiquitin ligase enzymes together for target ubiquitination and subsequent degradation by the cellular protein degradation machinery.
Because small molecule drugs have relatively simple structures, they are typically easily accessible via chemical synthesis. This chemistry accessibility enables synthetic and medicinal chemists to systematically alter small molecules’ structure and assess the effects of alterations on their physicochemical properties and biological activity. Structure-activity relationships (SAR) are a central concept in drug discovery.
What is a prodrug? Small molecule drugs are typically active in the form in which they are administrated. In certain cases however, the active form of the small molecule drug can have unfavorable properties, for example low stability, solubility, or cell permeability. These shortcomings can sometimes be overcome by chemically modifying the active form of the drug. The modified form of the drug is called a prodrug and usually has little or no activity. After administration, prodrugs are converted back to the active form via biological activation, for example after an enzymatic cleavage.
Other key properties of small molecule drugs are their oral bioavailability and good tissue penetration. The former enables small molecule drugs to be administrated orally, while the latter allows them to diffuse throughout the body and reach their target tissues and organs. These two properties are at least in part responsible for the success of the small molecule drug modality and are a clear advantage over other modalities, for example antibodies, which are typically not orally bioavailable and, due to their relatively large size, have limited tissue penetration.
What is drug tissue penetration? Drug tissue penetration refers to the ability of a drug to reach and distribute within specific tissues or organs in the body. It is an important concept because effective tissue penetration is essential for a drug to exert its therapeutic effects on target cells or tissues within a given anatomical site. The level of tissue penetration influences the drug's efficacy, bioavailability, and overall success in treating the intended disease condition.
Further, small molecule drugs are typically not immunogenic–they do not trigger the patient’s immune response–another key advantage over other modalities, for example, recombinant proteins and cell therapies, which are typically immunogenic and can easily trigger the patient’s immune response.
Machine Learning and Artificial Intelligence are Transforming Small Molecule Drug Discovery
Small molecule drug discovery is particularly well-positioned to benefit from recent advances and future developments in machine learning (ML) and artificial intelligence (AI). This is predominantly because small molecules’ structure is simple enough to be represented in a machine-readable format, many synthetic pathways are well understood, large amounts of data regarding the relationship between small molecule structures and its physicochemical properties and biological activity are available and can be obtained via structure-activity relationships. The two examples below illustrate some of the ways that ML and AI approaches can help enhance the efficiency of drug discovery and the development of new small molecule drugs.
ML and AI approaches can make the synthesis of small molecule drugs more efficient by enhancing chemistry retrosynthesis. Chemistry retrosynthesis is a process used in synthetic organic chemistry to work backward from a target molecule to identify the sequence of simpler precursor molecules or starting materials. It involves breaking down complex molecules into simpler building blocks, allowing chemists to design efficient synthetic pathways for the production of desired molecules. ML and AI approaches enhance chemistry retrosynthesis by leveraging large datasets of chemical reactions. ML and AI can predict reaction pathways, propose novel synthetic routes, and optimize conditions based on learned patterns.
ML and AI have a significant impact in the optimization of small molecules in drug discovery. One of the key stages in small molecule drug discovery is the optimization of promising compounds to improve the desired properties such as solubility, stability, cell membrane penetration, and potency among others. Typically, this is a demanding process of trial and error in which the compound’s structure is modified and the compound’s properties are evaluated. If the desired properties are improved, then the modification is kept and a new modification is introduced. If the desired properties are not improved, then the modification is discarded and a different modification is attempted. ML and AI approaches can carry on multi-parameter optimizations and, based on available data and learned patterns, can propose structural modifications that are likely to simultaneously improve desired properties.
Understanding the Limitations of Small Molecule Drug Modalities
Despite their tremendous success, small molecule drugs have a number of disadvantages and limitations. Their small size and relatively simple structure–the properties that contributed to their success in medicine–are also responsible for some of their limitations.
The relatively few chemical groups that small molecules have for target recognition and engagement do not allow small molecule drugs to discriminate very well between proteins with similar binding sites. For this reason, small molecule drugs can make unwanted interactions with off-targets and have associated specificity issues, sometimes leading to side effects and potential safety concerns.
Another limitation of small molecule drugs has to do with their mode of interaction with their targets. The low number of chemical groups within their structure and their relatively limited interaction surfaces limit the type of targets with which small molecule drugs can interact: they can typically only bind to targets with well-structured and deep binding pockets, for example enzymes, surface receptors, and ion channels. The large number of cellular processes mediated by protein-protein interactions and their relatively flat surfaces and shallow cavities are thus typically out of reach for conventional small molecule drugs. Similarly, intrinsically disordered proteins which typically lack well-structured domains or binding sites, are also poor targets for small molecule drugs. Small molecules with new mechanisms of action can partially overcome some of these limitations. For example, molecular glues, can stabilize protein-protein interactions via different mechanisms; when the interaction between a target protein and an effector protein is stabilized, the target can be modified by the effector.
An additional limitation of small molecule drugs also draws from one of their advantages – their tissue penetration properties also leads to limited tissue selectivity and specificity. For example, a small molecule inhibitor aimed at blocking a signaling pathway in tumors will also likely block the same pathways in normal tissues, resulting in potential side effects and toxicity. Novel drug modalities overcome this limitation by fusing small molecule drugs with other molecules that recognize specific tissues or organs for targeted delivery, such as antibody-drug conjugates (ADCs).
References
1. Beck, H., Härter, M., Haß, B., Schmeck, C., & Baerfacker, L. (2022). "Small molecules and their impact in drug discovery: A perspective on the occasion of the 125th anniversary of the Bayer Chemical Research Laboratory." Drug Discovery Today.
2. Fraterman, S., Xie, W., Wu, C., Thielmann, M., & Yudhistiara, B. (2023). "New Drug Modalities offer promise and peril." Boston Consulting Group.
3. Gurevich, E. V., & Gurevich, V. V. (2014). "Therapeutic Potential of Small Molecules and Engineered Proteins." Handbook of Experimental Pharmacology.
4. Hajar, R. (2011). "Statins: Past and Present." Heart Views.
5. Hutchings, M. I., Truman, A. W., & Wilkinson, B. (2019). "Antibiotics: Past, Present and Future." Current Opinion in Microbiology.
6. Liu, X., & Ciulli, A. (2023). "Proximity-Based Modalities for Biology and Medicine." ACS Central Science.
7. Volkamer, A., Riniker, S., Nittinger, E., Lanini, J., Grisoni, F., Evertsson, E., Rodríguez-Pérez, R., & Schneider, N. (2023). "Machine learning for small molecule drug discovery in academia and industry." Artificial Intelligence in the Life Sciences.
