Think back to the last time you took medicine — perhaps it was a pain reliever or some cough syrup. What were you thinking about as that medicine was digested? Chances are, you weren’t thinking about the origins of the drug, but scientists and doctors have probably spent countless hours developing it.
The task of getting a drug to your local pharmacy is complex, arduous, and frequently expensive. Pharmaceutical companies have established elaborate business models for the research, development, and production of molecules to treat diseases. The first phase of drug development involves laboratory experiments to discover and refine the drug, and the second phase is to test the drug in clinical trials to evaluate the drug’s safety and efficacy in patients.
Despite technological advances, there are fewer new medicines approved every year.
Many of the medicines developed in the last century were derived from naturally occurring molecules (natural products) found in sources including plants, bacteria, and fungi; as the discovery of these drugs slowed, man-made molecules have not filled the deficit. The challenge facing medicinal science is to fill the demand for new drugs.
Phase One: Drug Discovery
Drug discovery relies on the collaborative efforts of researchers including chemists, biologists, and physicians. Chemists build molecules that may eventually become drugs while biologists investigate the relevant molecules that cause diseases. Together, scientists select drug targets in the form of large biomolecules (such as proteins) or cancer cells, then search for molecules that will disrupt the protein or kill the malignant cell. Chemistry plays a vital role through its ability to decipher molecular interactions that define the way drugs cure diseases.
In a way, drug discovery is like searching for a molecular key (the drug) to open the disease’s lock. Scientists try to find out as much as possible about the structures of the key and lock as well as how different keys interact with the lock. To have a good fit and block the drug target’s function, the molecular key must be complementary in its geometric shape and its interactions with a cavity in the biomolecule. The challenge lies in finding a way to test the plethora of available keys against the vast number of accessible locks. To complicate matters more, a lock may not be found for every disease and one key may fit into multiple locks.
Drug Discovery: Natural Products
Historically, medicines were administered in the form of herbal concoctions, and many traditional medicines continue to be taken this way. As science advanced, chemists were able to extract the active ingredients from natural sources to make more potent medicines. For example, aspirin (acetylsalicylic acid) was discovered from the willow tree, the bark of which was used in traditional herbal remedies .
When a natural source is not readily available, chemistry often steps in to provide practical alternatives. In the early 1960s, the Pacific yew tree (Taxus brevifolia) was found to produce the blockbuster anticancer drug paclitaxel (Taxol) . Initially, Pacific yew populations declined because the harvesting process stripped the bark and killed the trees. Public outcry against this method led to an improved process that generated paclitaxel by isolating part of the molecule from European yew needles, which was then chemically modified to produce the complete drug. Currently, paclitaxel is produced by isolating plant cells from twigs and needles and growing the cells in a process called plant cell fermentation; this process is more sustainable because it spares trees and reduces chemical waste .
Drug Discovery: High-Throughput Screening
The first step in modern drug discovery typically involves a process called high-throughput screening, where thousands of molecules are tested at once for their efficacy against a certain drug target . In this technology, researchers use robots to mix miniscule amounts of potential drugs with tiny samples of the drug target. The collection of test molecules can include both man-made molecules and natural products. Through the screening process, a molecule may show potential as a drug by binding to the target biomolecule (i.e., the key for the lock) or killing diseased cells. An effective molecule identified this way is then elaborated into a potential drug through further screening with variants of the first molecule. If a more potent drug is found, the molecule is tested in cells and animals to mimic the drug’s behavior in humans. If the drug proves to be effective in laboratory studies, the next step is a clinical trial.
Phase Two: Clinical Trials
Clinical trials are the stage of drug development where a drug’s effect on humans is tested . Because the human body is more complex than a cell in the laboratory, a drug must be studied in a small population of patients before the US Food and Drug Administration (FDA) approves the drug for release to the general population. To forecast the “druglikeness” of a molecule, a set of molecular structure-based predictions were developed. Though these metrics are not requirements, they can approximate how the drug behaves in the body (e.g., toxicity) and how the body responds to the molecule (e.g. metabolism, absorption) . In clinical trials, the drug is primarily assessed for how effectively it treats the disease it is designed to target and whether it is safe for use by patients. At this second phase, often billions of dollars have already been invested in a drug’s discovery and development; this huge investment is a major part of the inherent financial risk in drug development.
Occasionally, the intended purpose of a drug is not its most effective function. For example, sildenafil (Viagra) was originally developed to treat high blood pressure (hypertension) and chest pain (angina) . When Viagra was in its first clinical trial, patients began asking for the drug even though the clinical trials had shown that it was ineffective for treating angina. Another clinical trial was carried out to study Viagra’s effects on erectile dysfunction and, ultimately, Viagra became the billion-dollar drug it is today.
Challenges Going Forward
As new technologies in genetics and disease identification become available , our understanding of the molecular basis for diseases will also improve. Unfortunately, the rate at which new diseases are emerging appears to be outrunning the pharmaceutical industry’s ability to find remedies. Furthermore, drugs can become ineffective through the evolution of resistance in certain diseases-causing bacteria, viruses, parasites, and cancers. For example, staph infections (Staphylococcus aureus) can become resistant to many antibiotics. These strains of staph are often referred to as Multi-drug-Resistant Staphylococcus aureus (MRSA) and require the use of strong antibiotics like vancomycin (called the “drug of last resort” because it causes kidney damage). Sadly, vancomycin-resistant strains of staph (VRSA) have emerged in the last 15 years and pose a major challenge to drug developers because even stronger antibiotics must be found .
Clearly, pharmaceutical scientists must intensify the search for effective drugs to treat these new diseases. However, many large pharmaceutical companies have cut their research and development programs, which have struggled to produce new drugs over the past decades . Fortunately, the federal government has recognized the urgency of the challenge facing drug discovery and created a new center for drug development at the National Institutes of Health . Drug discovery is a long, laborious process, and only time will tell whether the current strategies will be effective in producing viable remedies.
Jessica Wu is a PhD student in the department of Chemistry and Chemical Biology at Harvard University.
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