9.4 Drug discovery and development
3 min read•august 7, 2024
Drug discovery and development are crucial processes in biotechnology and medicine. They involve screening compounds, designing molecules, and using computational tools to identify potential new treatments. This complex journey aims to find safe, effective drugs for various diseases.
The drug development process includes preclinical studies, , and approval. It's a long, expensive journey from lab to market. Personalized medicine approaches, like , are revolutionizing treatment by tailoring therapies to individual genetic profiles.
Drug Discovery Techniques
Screening and Design Methods
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- rapidly assesses large numbers of compounds for potential therapeutic activity using automated equipment and robotics
- Enables testing of thousands to millions of compounds in a short period
- Identifies "hits" that show desired biological activity and can be further optimized into lead compounds
- Combinatorial chemistry generates large libraries of structurally related compounds for screening
- Uses automated synthesis methods to create diverse sets of molecules
- Allows exploration of a wide chemical space to identify novel drug candidates
- utilizes knowledge of the 3D structure of a drug target to rationally design compounds that interact with the target
- Employs techniques like X-ray crystallography and NMR to determine target protein structures
- Uses computational modeling to predict and optimize drug-target interactions (molecular docking)
Computational Approaches
- Bioinformatics plays a crucial role in modern drug discovery by analyzing and integrating biological and chemical data
- Helps identify and validate drug targets through genomic and proteomic analysis
- Assists in predicting drug-likeness, ADME properties (absorption, distribution, metabolism, excretion), and potential toxicity of compounds
- Facilitates virtual screening of large compound libraries to prioritize compounds for experimental testing
Drug Development Process
Preclinical Studies
- Preclinical studies assess the safety and efficacy of drug candidates before human testing
- Involves in vitro (cell-based) and in vivo (animal) experiments to determine pharmacological properties, toxicity, and therapeutic effects
- Pharmacokinetic and pharmacodynamic studies evaluate how the drug is absorbed, distributed, metabolized, and eliminated in the body (ADME properties)
- Toxicology studies assess potential adverse effects and determine safe dosage ranges
- Preclinical data is used to support an application to the FDA for permission to start human clinical trials
Clinical Trials
- Clinical trials are conducted in human volunteers to evaluate the safety, efficacy, and optimal dosing of a drug candidate
- Phase 1 trials assess safety and in a small group of healthy volunteers (20-100 participants)
- Phase 2 trials evaluate efficacy and side effects in a larger group of patients with the targeted disease (100-500 participants)
- Phase 3 trials are large-scale, randomized, controlled studies to confirm efficacy and safety in a broader patient population (1,000-5,000 participants)
- Compares the drug candidate to existing treatments or placebo
- Provides pivotal data for regulatory approval
FDA Approval Process
- After successful completion of clinical trials, a is submitted to the FDA for review
- The FDA evaluates the safety, efficacy, and manufacturing data to determine if the benefits outweigh the risks
- If approved, the drug can be marketed and prescribed to patients
- Post-marketing surveillance (Phase 4 studies) continues to monitor the drug's safety and effectiveness in the larger population
Personalized Medicine Approaches
Pharmacogenomics
- Pharmacogenomics studies how genetic variations influence an individual's response to drugs
- Analyzes genetic differences in drug-metabolizing enzymes, drug transporters, and drug targets
- Aims to predict efficacy, toxicity, and optimal dosing based on a patient's genetic profile
- Enables tailoring of drug therapy to maximize therapeutic benefits and minimize adverse reactions
- Example: Genetic testing for CYP2C9 and VKORC1 variants to guide warfarin dosing
Personalized Medicine
- Personalized medicine, also known as precision medicine, aims to customize healthcare based on an individual's genetic, lifestyle, and environmental factors
- Integrates genomic, clinical, and environmental data to develop targeted therapies and prevention strategies
- Example: Trastuzumab (Herceptin) for HER2-positive breast cancer, which is determined by genetic testing of the tumor
- Involves , which are tests that identify patients most likely to benefit from a specific therapy
- Example: EGFR mutation testing to select patients for EGFR inhibitors (gefitinib, erlotinib) in non-small cell lung cancer
- Personalized medicine has the potential to improve patient outcomes, reduce adverse reactions, and optimize healthcare resources by providing the right treatment to the right patient at the right time
Key Terms to Review (22)
Agonist: An agonist is a substance that binds to a specific receptor and activates it, leading to a biological response. This action can mimic the effects of naturally occurring substances in the body, such as hormones or neurotransmitters, effectively enhancing or initiating the signaling pathways associated with those receptors. Agonists play a critical role in drug discovery and development, as they can be designed to target specific receptors to treat various medical conditions.
Antagonist: An antagonist is a substance that binds to a receptor and blocks or dampens the biological response that would typically occur when an agonist binds to the same receptor. This action can be crucial in drug discovery and development, as antagonists can help to inhibit overactive pathways or counteract unwanted physiological effects caused by certain agonists. They are often used in therapeutic settings to modulate the activity of various biological systems.
Biomarkers: Biomarkers are biological indicators, often measured in the body, that provide information about a person's health status or the presence of disease. They play a crucial role in drug discovery and development by helping researchers identify potential therapeutic targets, monitor disease progression, and evaluate the effectiveness of treatments.
Clinical trials: Clinical trials are systematic studies conducted to evaluate the safety and efficacy of new treatments, drugs, or therapies in human participants. These trials are crucial for advancing medical knowledge and ensuring that new interventions are safe before they are approved for widespread use. The process typically includes multiple phases, each designed to answer specific research questions about the intervention’s effects, optimal dosages, and overall impact on health.
Companion diagnostics: Companion diagnostics are medical devices or tests designed to determine the suitability of a specific drug for a patient based on their individual characteristics, such as genetic makeup. These diagnostics play a crucial role in personalizing treatment options, ensuring that patients receive therapies that are most likely to be effective for them, thus improving outcomes in drug discovery and development.
Double-blind study: A double-blind study is a research design in which neither the participants nor the researchers know which individuals are receiving the treatment and which are receiving a placebo. This approach helps to eliminate bias in both the administration of the treatment and the interpretation of results, ensuring that outcomes are based solely on the effects of the intervention being tested.
EMA: EMA stands for the European Medicines Agency, which is an agency of the European Union responsible for the evaluation and supervision of medicinal products. It plays a vital role in ensuring that all medicines available in the EU are safe, effective, and of high quality, directly impacting the processes involved in drug discovery and development, as well as establishing regulatory frameworks for biotechnology products.
FDA: The FDA, or Food and Drug Administration, is a federal agency of the United States Department of Health and Human Services responsible for protecting public health by ensuring the safety and efficacy of food, drugs, cosmetics, and medical devices. The agency plays a crucial role in the approval and regulation of biotechnology products, including transgenic plants, pharmaceuticals, and various biotechnological innovations. By establishing guidelines and regulations, the FDA ensures that these products meet safety standards before they can be marketed to the public.
High-throughput screening: High-throughput screening is a method used in molecular biology and drug discovery that allows researchers to quickly conduct millions of chemical, genetic, or pharmacological tests. This technology accelerates the process of identifying active compounds, antibodies, or genes that modulate a particular biomolecular pathway, making it invaluable for advancements in protein engineering, drug development, and emerging biotechnologies.
Investigational New Drug (IND): An Investigational New Drug (IND) is a substance that has been submitted to the FDA for authorization to begin clinical trials on humans. It marks a significant milestone in drug development as it transitions from laboratory research to clinical testing, where its safety and efficacy will be evaluated. The IND application includes data from preclinical studies and must meet strict regulatory standards before any human trials can commence.
Lead Optimization: Lead optimization is the process of refining and enhancing the properties of a lead compound to improve its efficacy, selectivity, and safety as a potential drug candidate. This stage is critical in drug discovery and development as it focuses on transforming a promising lead into a drug that meets the necessary criteria for clinical trials and eventual market approval.
Liposomes: Liposomes are small spherical vesicles composed of lipid bilayers that can encapsulate drugs, proteins, or other therapeutic agents. They serve as drug delivery systems that enhance the solubility, stability, and bioavailability of pharmaceuticals, allowing for targeted and controlled release in the body.
Monoclonal antibodies: Monoclonal antibodies are laboratory-made molecules engineered to bind specifically to target antigens, which are substances that induce an immune response in the body. These antibodies are derived from a single clone of immune cells and can be used in various applications such as diagnostics, treatment of diseases, and research. Their specificity makes them powerful tools in medicine and biotechnology, impacting areas like therapeutic development and emerging technologies in healthcare.
Nanoparticles: Nanoparticles are tiny particles that measure between 1 and 100 nanometers in size, which is about 1/100,000th the width of a human hair. Their small size allows them to exhibit unique physical and chemical properties, making them highly useful in various applications, including drug delivery, diagnostics, and therapeutics. They have the potential to enhance drug efficacy and reduce side effects, and are a cornerstone in the development of innovative biotechnological solutions.
New drug application (NDA): A new drug application (NDA) is a formal proposal submitted to regulatory authorities, such as the FDA in the United States, requesting approval for a new pharmaceutical drug to be marketed and sold. This application includes comprehensive data from clinical trials, information on drug formulation, manufacturing processes, labeling, and proposed usage. The NDA is a critical step in the drug discovery and development process, as it represents the culmination of extensive research aimed at ensuring the safety and efficacy of a new drug before it reaches consumers.
Pharmacogenomics: Pharmacogenomics is the study of how an individual's genetic makeup affects their response to medications. It combines pharmacology, the study of drugs, and genomics, which is the study of genes and their functions, to optimize drug therapy based on a person's genetic profile. This field aims to enhance the effectiveness and safety of medications by tailoring treatments to the unique genetic characteristics of each patient.
Pharmacokinetics: Pharmacokinetics is the branch of pharmacology that studies how an organism affects a drug, focusing on the processes of absorption, distribution, metabolism, and excretion (ADME). This term is crucial in drug discovery and development, as understanding pharmacokinetics helps researchers determine the right dosage, delivery methods, and timing for medication to ensure maximum efficacy and minimal toxicity.
Preclinical testing: Preclinical testing refers to the phase of drug development that occurs before a new drug is tested in humans, typically involving laboratory and animal studies to assess the safety, efficacy, and biological activity of a compound. This crucial step helps researchers gather data that supports moving forward to clinical trials, ensuring that only the most promising candidates reach human testing.
Randomized control trial: A randomized control trial (RCT) is a scientific study design that randomly assigns participants into two or more groups to test the effects of an intervention, such as a drug or treatment, compared to a control group. This method helps eliminate bias and establishes a clear cause-and-effect relationship, making it a gold standard in clinical research, especially in drug discovery and development.
Statins: Statins are a class of drugs used to lower cholesterol levels in the blood by inhibiting the enzyme HMG-CoA reductase, which plays a central role in cholesterol biosynthesis. They are crucial in reducing the risk of cardiovascular diseases and have been extensively studied and developed through drug discovery processes, showcasing the importance of targeted therapies in modern medicine.
Structure-based drug design: Structure-based drug design is a method used in the development of new pharmaceutical compounds by analyzing the three-dimensional structure of biological macromolecules. This approach leverages the detailed knowledge of molecular structures to identify potential drug candidates that can effectively interact with specific targets, such as proteins or enzymes, thus enhancing the efficiency and effectiveness of drug discovery and development.
Target Identification: Target identification is the process of discovering and validating biological molecules, such as proteins or genes, that are implicated in a disease and can be potential targets for drug development. This step is crucial as it helps researchers focus their efforts on the right biological pathways and mechanisms to develop effective therapeutic agents.