The process of drug discovery, design and development is lengthy and takes more than fifteen years from bench to bedside. It is also expensive and requires a tremendous level of funding. Researchers spend countless hours working to create drugs that will impact human health and increase our immune system's effectiveness in fighting disease and pathogens. This section will highlight the drug design and development process.
Drug Discovery
The first step in the drug discovery process is to understand the disease that is going to be treated or targeted
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. Researchers begin this pre-discovery process by trying to understand the mechanics of a disease and the impact the disease has on genes and proteins in living cells
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. Once the disease is understood, researchers begin drug discovery by testing compounds that might interact with the previously identified disease proteins and molecules. Researchers do not work blindly, but instead test "lead compounds" that have been screened and are candidates that are safe and effective
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. Lead compounds meet several conditions, such as: being absorbed by the bloodstream, distributed to the proper site in the body, being metabolized efficiently, successfully excreted from the body, and non-toxic
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. Lead compounds can be found in three ways: nature, de novo and high-throughput screening processes
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. Lead compounds can be found in nature from bacteria, fungi or other sources. De novo research involves creating molecules using computer modeling. High throughput screening is when hundred of compounds are tested to check their compatibility with the target compound
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. Regardless of the discovery method that is chosen, lead molecules are ones that will interact with the target molecule from the disease and impact its effectiveness.
Once a candidate drug is found, it is optimized in the research lab to make it safer and more effective
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. This is an early stage of drug development, but researchers begin to think about how they would create the drug for human use, how it would be delivered in the body, and what large-scale manufacturing would look like for the compound. The drug then enters preclinical trials where it is tested in the lab and on animals to determine if it is safe for human testing
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. The discovery process and preclinical trials can take anywhere from three to six years to find a drug that will be suitable for human testing.
Drug Development
Once a drug is approved from preclinical trials it will enter the development process, which has many stages. The first is Phase 1 Clinical Trials, where the drug is tested on a small group of healthy human volunteers to determine if the drug is safe
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. Then, Phase 2 Clinical Trials are tests on a small group of patients impacted by the disease or condition being targeted in the study. This phase will determine if the drug is working and the risks and side effects it produces
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. The drug then moves into Phase 3 Clinical Trials where it is tested on a large group of individuals to determine if it is statistically beneficial and working as expected
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. Phase 3 is the longest part of the clinical trials and drugs that pass this phase apply for approval with the FDA. The clinical trial process can take up to 6 or 7 years to complete.
Once approved, the drug moves into the manufacturing process where it is manufactured on a large scale and distributed. Drugs also enter Phase 4 Trials, where ongoing research continues to determine efficacy and safety
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. Drug approval and manufacturing can take up to two additional years. The image below reviews the timeline for drug discovery and development.
Case Study: The HIV Virus
The drug design process outlined above utilizes structure-based drug design to determine possible candidates. One of the first and most successful structure-based drug design projects was the development of a drug for HIV virus.
HIV, the human immunodeficiency virus, is a virus that attacks human immune cells and causes AID, or acquired immunodeficiency syndrome. HIV is a major killer worldwide and researchers have spent many years trying to understand this deadly disease. Structural biology and structure-based drug design has been at the forefront of understanding the disease and finding a treatment
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. HIV is retrovirus, which means that its genetic material is RNA that can enter a cell and be transcribed into DNA
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Research has identified an HIV protease, which is a protein that is essential for HIV's life cycle and development
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. The protease is made up of two equal halves, and has an active site in the center
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. This protease has become the target of HIV research and structure-based drug design has focused on finding a way to block the enzyme to prevent it from spreading in the body
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. Researchers used the drug design and discovery process outlined in the previous section to determine what molecule could be used to block this active site and inhibit the molecule. They tested many lead molecules that were found through online chemical libraries and trial-and-error testing. Through the drug design process, scientists found a protease inhibitor that was able to theoretically block the HIV virus from spreading in the body
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. The process took several years and the drug had to see if it met the requirements for being a viable drug. Unfortunately, the first inhibitor was not able to be absorbed the body so therefore would not be an effective drug for human use
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. Researchers continued and have found some protease inhibitors that work as antiviral therapy, and although they do not cure HIV/AIDS, they are a breakthrough in structure-based drug development
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. Researchers continue to look for these structural compounds that could inhibit the action of many viruses that impact humans.
