9.4 Drug discovery and development

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, clinical trials, and FDA approval. It's a long, expensive journey from lab to market. Personalized medicine approaches, like pharmacogenomics, are revolutionizing treatment by tailoring therapies to individual genetic profiles.

Drug Discovery Techniques

Screening and Design Methods

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• High-throughput screening 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
• Structure-based drug design 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 Investigational New Drug (IND) 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 pharmacokinetics 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 New Drug Application (NDA) 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 companion diagnostics, 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