The human body is a testament to nature’s remarkable ability to engineer complex organisms. Driving the body’s diverse biological functions are molecular machines known as proteins. Instructions for making proteins are encoded as sequences of DNA, these sequences are called genes. An organism's genome refers to the complete collection of its genes. Fundamental biological processes called transcription and translation convert a gene’s instructions into an ordered assembly of amino acids (amino acids are the building blocks of proteins). Amino acids are linked together into chains, that twist and fold into complex structures that can be further modified to give rise to functional proteins that initiate, regulate, and execute the essential processes required for life.
From supporting the transfer of information between nerves, to the generation of antibodies that keep us safe from disease-causing pathogens, hardly anything occurs in the body without being facilitated or conducted by proteins. Given their prominent role in biology, it follows that many common (e.g. cardiovascular, cancer) as well as rare/orphan (e.g. cystic fibrosis, myotubular myopathy) diseases can be linked to defective or dysregulated proteins. A well-documented example is the breast cancer type 1 susceptibility protein (BRCA1), an often mutated protein in breast and ovarian cancers. Normally, BRCA1 deters the onset of cancer by facilitating the repair of damaged DNA, so that harmful changes to genes are not amplified. When mutated, BRCA1 loses its ability to repair damaged DNA, allowing cancer-promoting mutations to accumulate until the disease fully manifests itself.
Due to their direct connection to biological function and disease, civilizations have long relied on medicines that, unknown to them at the time, target proteins to treat illnesses. Salicylic acid, named after the Greek word for willow tree, has long been isolated from willow bark to treat pain and inflammation since ancient Sumer. This small molecule continues to be used to this day in the form of acetylsalicylic acid (ASA), the active pharmaceutical ingredient in Aspirin. Interestingly, ASA’s specific mode of action was not elucidated until the 1970s, when scientists observed that it irreversibly inhibited the action of a protein called cyclooxygenase. Cyclooxygenase controls the production of a biological molecule that regulates pain and inflammation, thus explaining Aspirin’s pain and fever reducing effects. Today, almost all cancer chemotherapeutics interact with key proteins that drive cancer progression with the intent of modifying or inhibiting their functions.
Scientists have used many diverse approaches to drive the discovery of the next big drug for both common and rare diseases. Recently, there has been a resurgence in testing a large number of compounds against biological models that serve as proxies for a disease state. Chemicals that cause a desired outcome in these models are classified as hits, and become the starting points for a drug molecule. This type of testing, called phenotypic screening, has become more efficient with the advent of robotics and automation, but due to the nature of the testing, the underlying biological mechanism driving the positive the results is often unknown. In order for a hit molecule to become a drug, understanding how it interacts with proteins and influences biology is essential. Further, “repurposing” of existing, safe therapeutics has become a novel paradigm which can facilitate translation of scientific discoveries into the clinic.
Scientists have many techniques for uncovering which proteins are being affected by a potential small molecule. However, knowing which proteins to test in the first place can be difficult, leading to numerous costly experiments. Understanding which proteins are likely interacting with a small molecule can help streamline this decision making, allowing scientists to choose the right experiments and progress their drug candidate along. Modeling the biophysical structure of proteins on a computer and virtually predicting their interactions with a potential therapeutic can provide researchers with a insights into the proteins likely interacting with a drug candidate. Protein structures can now be determined from several techniques, with the X-ray crystallography representing a technique that has resulted in many of the structures available today.
While computational power has advanced steadily since docking experiments first began in the 1980s, probing all protein structures remains a challenge. Cyclica’s Ligand Express™ platform uses advanced bioinformatics algorithms to first select protein structures that are likely to be complementary to the drug being screened, thereby enhancing the specificity of predicted drug-protein interactions and greatly reducing time and resources needed to generate high-confidence results. Cyclica can provide a short list of proteins that are likely interacting with a small molecule, giving scientists the insights they need to make better research decisions.
The medical landscape has changed significantly since antiquity as scientists continue to find novel avenues to treat rare and common diseases. Despite the advent of cell therapy, biologics, and even gene therapy, small molecule drugs will continue to have an immediate tremendous impact on human health. Compared to other types of therapies, small molecule drugs are cheaper to manufacture, easier to administer, and directly affects the functional proteins underlying the disease. Cyclica contributes to the development of future small molecule therapeutics for both common and rare diseases by greatly reducing the time, cost, and risk associated with generating, prioritizing and evaluating novel therapeutics for use in the clinic.
This blog was written by Tonny Huang, a graduate student at the Princess Margaret Cancer Center. Tonny has a deep interest in the applications of protein science for the betterment of human health. You can find him here on LinkedIn.
1. Couch, F. J., Nathanson, K. L., Offit, K. Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 343, 1466–1470 (2014).
2. Goldberg, D. R. (2008) Aspirin: Turn of the Century Miracle Drug. In R. J. Giguere (Ed.), Molecules that Matter (pp. 19-32). Philadelphia, PA: Chemical Heritage Foundation.
3. Vane, J. R., Botting, R. M. The mechanism of action of aspirin. Thromb Res 110, 255-258 (2003).
4. Reddy, A. S., Zhang, S. Polypharmacology: drug discovery for the future. Expert Rev Clin Pharmacol 6 (2013).