Introduction to Dug Discovery
Key Topics.
Instructor's Background: Undergraduate Biology, Master's Biology, PhD Pharmacology.
Drug Discovery:
Serendipity and Luck: A significant factor in drug discovery (e.g., penicillin).
Nature as a Source: Many drugs derived from plants (e.g., ephedra/pseudoephedrine, opium/morphine, cinchona/quinine, willow bark/aspirin).
Historical Examples:
Ephedra vulgaris (3000 BC China) -> Ephedrine/Pseudoephedrine (Sudafed). Pseudoephedrine can be converted to methamphetamine.
Opium poppy (Ancient Greeks) -> Morphine, Codeine (addictive, powerful pain relievers). Morphine can be converted to heroin. Poppy seeds can cause positive drug tests.
Cinchona tree bark (Middle Ages) -> Quinine (malaria treatment).
Willow tree bark (Middle Ages) -> Salicylic acid -> Aspirin.
Alexander Fleming and Penicillin (1928): Accidental discovery when mold killed bacteria on a petri dish. Penicillin (from Penicillium notatum mold) is a critical antibiotic, saving millions of lives (e.g., in WWII). Mold produces antibiotics as a defense mechanism.
Drug Repurposing: Using an existing drug for a new indication.
Minoxidil: Originally for hypertension, caused hair growth, repurposed as Rogaine (for hair loss). Grants another 20 years of patent.
Sildenafil Citrate: Originally for hypertension/angina, caused erections, repurposed as Viagra (for erectile dysfunction).
Drug Discovery Process:
Target Identification: Understanding disease mechanisms (e.g., hypertension: blocking enzymes, neurotransmitter receptors, ion channels).
DNA and Protein Defects: Defective DNA leads to defective proteins, causing disease (e.g., cystic fibrosis, cancer).
Transgenic Mice: Mice engineered with human genes (normal or defective) to study gene function and disease.
High-Throughput Screening:
Mimicking biological reactions in small wells (384-well plates).
Testing millions of chemical compounds to find activity (inhibition/enhancement).
Automated using robots, significantly speeding up the process (from 1.5 years to 2 weeks for millions of compounds).
Chemical Structures: Many drugs contain benzene rings, which can interact with protein grooves.
Lead Optimization:
Verify "hits" (active compounds).
Test in cell cultures.
Test in animal models of disease (e.g., inducing hypertension in animals).
Chemists improve potency, reduce toxicity, enhance solubility, improve bioavailability (resistance to stomach acid, liver metabolism).
Animal Testing:
Necessity: Alternatives are human testing.
Ethical Considerations: Lab animals are bred in captivity, not wild-caught; monitored by vets; pain management required by law.
FDA Requirement: All drugs must be tested in at least two animal species before human trials.
Clinical Trials (Human Testing):
Minimum three phases required.
Animal safety does not guarantee human safety (e.g., drug fatal to humans despite being safe in monkeys).
Drug Development Timeline and Cost:
Time: 9-16 years from discovery to FDA approval.
Patents: Last 20 years from discovery date. This leaves 4-11 years of market exclusivity for the pharmaceutical company.
Cost: Approximately $3 billion to develop and get a drug approved.
Success Rate: Only 2 out of 10 FDA-approved drugs recover their R&D costs.
Pricing: High drug prices reflect R&D costs, not manufacturing costs.
Blockbuster Drugs: Drugs that generate billions in revenue (e.g., Keytruda, Mounjaro/Zepbound, Ozempic/Wegovy).
Most Prescribed Drugs (US):
Lipitor (cholesterol)
Norvasc (blood pressure)
Synthroid (thyroid deficiency)
Most Abused Drugs (World):
Alcohol
Nicotine
Marijuana
Opioids
Homework Assignment: Watch TV commercials and list advertised drugs (due next week).
Brand Name vs. Generic Name:
Brand Name: Company's marketing name (e.g., Tylenol, Advil, Band-Aid, Ping-Pong, Xerox, Chapstick, Kleenex, Coke, Scotch Tape). Starts with uppercase.
Generic Name: Government-assigned chemical name (e.g., acetaminophen, ibuprofen, bandage, table tennis, copier, lip balm, tissue, cola, adhesive tape). Starts with lowercase.
Purpose of brand names: Marketing, memorability, distinction.
FDA uses generic names in correspondence to avoid free advertising.
Reasons for Drug Failure in Clinical Trials:
Efficacy (40%): Does not work well enough.
Safety (30%): Unacceptable side effects. (Side effects are relative to disease severity; cancer treatment side effects are tolerated more than for minor ailments).
Economics: Not financially viable (e.g., common cold cure too expensive for consumer acceptance).
Types of Drugs:
Small Molecule Drugs: Most common, 30-40 atoms (e.g., aspirin).
Peptides: Chains of amino acids (e.g., insulin).
Proteins/Monoclonal Antibodies: Very large complex molecules.
Thalidomide Tragedy (1950s-60s):
Drug given to pregnant women for anxiety/nausea in Europe.
Resulted in 20,000 babies born without limbs due to the drug crossing the placenta.
Dr. Frances Kelsey at the FDA prevented its approval in the US, earning the Congressional Medal of Freedom. This led to increased understanding of drug effects on fetuses.
Drug Discovery & Development
Overview
This handout explores the fascinating, complex, and often serendipitous process of drug discovery and development. Understanding this process reveals the significant investment in time, resources, and ethical considerations required to bring life-saving medications to market.
Key Concepts
Serendipity (Luck/Accident): A significant factor in drug discovery, where valuable findings occur by chance, often building on innovative research.
Repurposing: The act of identifying new uses for existing drugs, leading to new indications and extended patent life.
Mechanism of Action (MOA): How a drug works at a molecular or cellular level to produce its therapeutic effect.
Enzymes: Proteins in the body that catalyze biochemical reactions. Drugs can target enzymes to block or enhance these reactions.
Hormones/Neurotransmitters: Chemical messengers that bind to receptors (e.g., on the heart) to regulate bodily functions. Drugs can block or mimic these to alter physiological responses.
Ion Channels: Pores in cell membranes that allow ions (e.g., calcium) to pass through, crucial for muscle contraction and nerve impulses. Drugs can modulate these channels.
DNA, Genes, Proteins: DNA contains the blueprint for proteins. Defective genes lead to defective proteins, causing disease.
Transgenic Mice: Mice engineered to carry and express human genes (or defective genes) to study disease mechanisms and drug effects.
High-Throughput Screening (HTS): Automated process using robots to rapidly test millions of chemical compounds against a specific biological target to find potential drug candidates.
Solubility & Bioavailability:
Solubility: A drug's ability to dissolve.
Bioavailability: The proportion of a drug that enters the circulation unchanged and is available to exert its effects. Affected by factors like stomach acid and liver metabolism.
Brand Name vs. Generic Name:
Brand Name: Marketing name given by the company (e.g., Tylenol, Advil, Band-Aid, Ping Pong, Xerox).
Generic Name: Government-assigned name (e.g., acetaminophen, ibuprofen, bandage, table tennis, copier). Generic names are always lowercase, brand names uppercase.
Patent Life: Drugs are patented for 20 years from discovery. This period covers research, development, and market time, often leaving only 4-11 years of exclusive market protection.
Blockbuster Drug: A drug that generates over $1 billion in annual sales.
Main Insights
Drug discovery is a lengthy and expensive process: It takes 9-16 years and approximately $3 billion to develop and approve a new drug.
Ethical considerations in animal testing: While controversial, animal testing is legally required by the FDA (on at least two animal species) before human trials to ensure safety, as animals are bred for this purpose and monitored for pain. Alternatives are currently insufficient.
Randomness and Observation: Many significant drug discoveries, like penicillin, arose from accidental observations.
Repurposing adds value: Finding new indications for existing drugs extends patent life and generates significant revenue (e.g., Minoxidil to Rogaine, Sildenafil to Viagra, Semaglutide for diabetes and weight loss).
Disease understanding drives drug development: Identifying the specific biological processes (e.g., enzyme activity, hormone binding, ion channel function) involved in a disease is crucial for developing targeted therapies.
Liver and stomach acid impact drug efficacy: The body's natural defense mechanisms (stomach acid, liver metabolism) break down foreign compounds, necessitating specific drug formulations and dosing schedules.
High failure rate: Most drug candidates fail during clinical trials, primarily due to lack of efficacy (40%) or safety concerns (30%). Economic viability also plays a role.
Side effects are relative: The acceptability of side effects depends on the severity of the disease. Life-threatening conditions may tolerate more severe side effects.
Thalidomide Tragedy: A historical example (1950s-60s) of severe birth defects caused by a drug (thalidomide) prescribed to pregnant women, highlighting the critical importance of rigorous drug testing and the understanding of placental transfer. This led to stronger FDA regulations, notably championed by Francis Kelsey.
Problems, Mistakes, and Pitfalls
Cheating and phone use in class: Distracting and disrespectful.
Dishonesty about absences: Better to be truthful.
Ignoring a drug's patent and intellectual property: Not patenting a discovery immediately risks theft.
Underestimating the cost and time of R&D: The significant investment in drug development often leads to high drug prices.
Lack of efficacy or safety: The primary reasons drugs fail clinical trials.
Economic non-viability: Even effective drugs (e.g., common cold cure) may not be marketed if production costs make them unaffordable to the public or if the market isn't willing to pay.
Misconceptions about drug testing: Animal testing is often misunderstood; it's a necessary step with ethical oversight.
Ignoring drug interactions with biological processes: Failure to account for stomach acid, liver metabolism, or placental transfer can have severe consequences.
Solutions & Best Practices
Communication: Text or email instructors about absences.
Proactive Learning: Utilize review materials provided for exams.
Participation: Ask questions and engage in discussions to deepen understanding.
Strategic Study Habits: Focus on provided review materials rather than excessive note-taking on non-essential content.
Rigorous Testing: Conduct thorough preclinical animal studies and multi-phase clinical trials to ensure safety and efficacy.
Utilize Technology: Employ robotic high-throughput screening to accelerate the initial drug discovery phase.
Chemical Optimization: Chemists continuously work to improve drug potency, reduce toxicity, enhance solubility, and increase bioavailability.
Ethical Oversight: Adhere to strict guidelines for animal testing (veterinary monitoring, pain management) and human clinical trials.
Practical Examples
Ephedra/Pseudoephedrine/Methamphetamine: Ephedra vulgaris used in 3000 BC for coughs/colds. Ephedrine and pseudoephedrine are derived from it. Pseudoephedrine (Sudafed) can be chemically converted to methamphetamine, leading to sales restrictions.
Opium/Morphine/Heroin: Ancient Greeks used opium for pain relief. It contains naturally occurring morphine and codeine (powerful, addictive opioids). Morphine can be converted to heroin. Poppy seed consumption can lead to positive drug tests for opioids.
Chinchona Tree Bark/Quinine: Used in the Middle Ages to treat malaria, still effective today.
Willow Tree Bark/Aspirin: People chewed willow bark for pain relief due to salicylic acid, which is converted to acetylsalicylic acid (aspirin). Bayer later commercialized aspirin.
Penicillin: Discovered by Alexander Fleming (1928) when mold (Penicillium notatum) accidentally grew on a bacterial culture, inhibiting bacterial growth. This led to the discovery of antibiotics, saving millions of lives (e.g., 6 million in WWII).
Minoxidil (Rogaine): Originally for hypertension, repurposed when a side effect of hair growth was observed. Now sold as Rogaine for baldness.
Sildenafil (Viagra): Originally for hypertension/angina, repurposed when a side effect of erections was observed. Now sold as Viagra for erectile dysfunction.
Cystic Fibrosis: Caused by a mutation in the CFTR gene, leading to defective protein function and excessive mucus production.
Cancer: A direct result of mutations in genes.
Transgenic Mice: Mice engineered with a firefly luciferase gene glow in the dark, demonstrating the ability to insert and express foreign genes.
Drug Economics (Common Cold Cure): A highly effective cold cure was not marketed because its projected cost ($100/day in 1994) was deemed economically unsound for a common, self-limiting illness.
Thalidomide: Prescribed for anxiety/nausea in pregnant women in the 1950s/60s, caused severe limb deformities in 20,000 babies. Never approved in the US due to Francis Kelsey's skepticism.
Historical Perspectives of Drug Discovery
Ancient Discoveries (Thousands of Years Ago):
Ephedra Vulgaris (3,000 BC, China): Used for coughs and colds.
Contains Ephedrine.
Pseudoephedrine: Modern-day Sudafed (used for stuffy noses), derived from ephedrine.
Methamphetamine: Simple chemical reaction from pseudoephedrine (explains restrictions on Sudafed purchases).
Opium (Ancient Greeks): From poppy plants.
Contains morphine and codeine (powerful, addictive pain relievers).
Morphine can be converted into heroin.
Used in combat for instantaneous pain relief.
Poppy seed consumption can lead to positive opioid drug tests.
Cinchona Tree Bark (Middle Ages): Contains quinine, used to treat malaria (still in use).
Willow Tree Bark (Middle Ages): Chewed for pain relief.
Contains salicylic acid, which is converted to aspirin (acetylsalicylic acid).
Bayer commercialized aspirin in the 1900s, originally from the willow tree.
Serendipitous Discoveries:
Alexander Fleming (1928) - Penicillin:
Discovered mold (Penicillium notatum) growing on a bacterial plate, inhibiting bacterial growth.
Led to the discovery of antibiotics (penicillin), one of the most significant medical advancements.
Saved an estimated 6 million lives in World War II.
Mold produces penicillin as a defense mechanism against bacteria.
Repurposing Existing Drugs:
Minoxidil (Rogaine):
Originally for hypertension, but noted to cause hair growth as a side effect.
Repurposed as a topical treatment for baldness (Rogaine).
Repurposing extends patent life for an additional 20 years.
Sildenafil Citrate (Viagra):
Originally for hypertension and angina.
Clinical trials showed a side effect of increased erections in males.
Repurposed for erectile dysfunction (Viagra).
Also extended patent life and generated billions in revenue.
Modern Drug Discovery Process
Foundation: Innovative research and science.
Target Identification:
Study diseases thoroughly (patients, genetics, animal models).
Animal Testing (Ethical Considerations):
Necessity: Animals or humans must be tested first; animals offer a safer initial option.
Animal Welfare: Lab animals are typically born and bred in controlled environments, not accustomed to the wild.
Regulation: Monitored by vets; laws prohibit inflicting pain without medication.
FDA Requirement: All drugs must be tested in two animal species before human trials.
Analogy: Drug saves lives due to animal testing (e.g., 10 rats, 5 mice, etc.).
Drug Design and Screening:
Goal: Find molecules that block or enhance biological processes related to disease.
High-Throughput Screening:
Mimic biological reactions in small test tubes (e.g., 384-well plates).
Screen millions of chemical compounds for activity (inhibition or enhancement).
Robotic systems now automate this process, reducing screening time from years to weeks.
Common Chemical Structures: Many drugs contain a "benzene ring" structure, which can fit into protein grooves to alter function.
Post-Screening Steps:
Confirmation: Repeat "hits" (compounds showing activity).
Cellular Testing: Test active compounds in cells with the target protein.
Animal Models: Administer promising compounds to animals with induced diseases (e.g., high-salt diet for hypertension) to observe effects.
Chemical Optimization: Chemists refine compounds for:
Potency: Increased effectiveness.
Non-toxicity: Reduced harmful side effects.
Solubility/Bioavailability:
Ability to survive stomach acid and liver metabolism.
Sufficient duration in the body (e.g., at least a few hours) to be a practical drug.
Transition to Human Trials (Clinical Trials):
Trigger: If safe and effective in animals.
Phases: At least three rounds of clinical trials required.
Risk: Animal safety does not guarantee human safety (e.g., autoimmune drug failure in humans).
Financial and Regulatory Aspects of Drug Development
Timeline: 9-16 years to develop and approve a drug.
Patents:
Must be patented the day of discovery.
Patent lasts 20 years.
Effective protection period is 4-11 years due to development time.
Repurposing a drug grants another 20 years of patent life.
Cost: Approximately $3 billion to get a drug approved.
Success Rate: Only 1 in 10 drugs going to the FDA recovers R&D costs.
Justification for High Prices: Covers extensive research, development, and high failure rates.
"Blockbuster" Drugs: Highly successful drugs generating billions in revenue annually.
Examples: Keytruda (cancer), Mounjaro (type 2 diabetes/weight loss), Ozempic (type 2 diabetes/weight loss), Dupixent (allergic reactions), Skyrizi (psoriasis), Eliquis (blood thinner), Darzalex (cancer), Biktarvy (HIV).
Most Prescribed Drugs (US):
Lipitor (cholesterol, generic: atorvastatin)
Norvasc (blood pressure, generic: amlodipine)
Synthroid (thyroid deficiency, generic: levothyroxine)
Others: Prilosec (reflux), Metformin (diabetes), Zoloft (depression/anxiety), Amoxicillin (antibiotic).
Most Abused Drugs (World):
Alcohol
Nicotine
Marijuana
Opioids
Brand Name vs. Generic Drugs
Brand Name: Marketing name assigned by a company (starts with uppercase).
Generic Name: Name assigned by the government (starts with lowercase).
Purpose of Brand Names:
Distinguish from competitors.
Attract and engage the public.
Aid in memorability (e.g., Band-Aid, Scotch Tape, Xerox, Chapstick, Kleenex, Coke, Ping Pong).
FDA Practice: Always uses generic names in correspondence to avoid free advertising.
Reasons for Drug Failure in Clinical Trials
Efficacy (40%): Does not work well enough.
Safety (30%): Unacceptable side effects.
Contextual: Severity of side effects is relative to the disease (e.g., cancer vs. pimple treatment).
Economics (20%): Not financially viable.
Example: Common cold cure not marketed due to high cost ($100/day in 1994) and lack of insurance coverage.
Types of Drugs
Small Molecule Drugs: Most common type, composed of 30-40 atoms (e.g., aspirin).
Peptides: Chains of amino acids (e.g., insulin).
Proteins: Larger, more complex molecules.
Monoclonal Antibodies: Largest protein drugs (e.g., for specific cancers).
Historical Tragedy: Thalidomide
Context (1950s-60s): Drug given to pregnant women for anxiety and morning sickness in Europe.
Consequence: Caused 20,000 babies to be born without limbs (thalidomide babies).
Misconception: Belief that drugs could not cross the placenta.
US Exception: Dr. Frances Kelsey at the FDA blocked its approval, earning the Congressional Medal of Freedom.
Broader Lesson: Emphasized that substances like alcohol and nicotine also cross the placenta, highlighting the need for caution during pregnancy.
The top 10 selling drugs mentioned in the audio are:
Ketruda (cancer drug)
Manjaro (for type 2 diabetes and weight loss, marketed as Zepbound for weight loss)
Ozempic (for type 2 diabetes and weight loss, marketed as Wegovy for weight loss)
Dupixent (for severe allergic reactions)
Skyrizi (for psoriasis)
Eliquis (blood thinner, anticoagulant)
Darzalex (for specific cancer)
Biktarvy (for HIV)
Zepbound (weight loss, same drug as Manjaro)
Wegovy (weight loss, same drug as Ozempic)
Final Takeaways
Drug development is a high-risk, high-reward endeavor driven by scientific research, accidental discoveries, and rigorous testing.
Understanding the underlying biological mechanisms of disease is fundamental to designing effective therapies.
Ethical considerations and regulatory oversight (FDA) are paramount to ensuring drug safety and efficacy.
The high cost of prescription drugs reflects the immense investment in research, development, and the high failure rate of candidates.
Differentiate between generic and brand names, recognizing the marketing power of brand names.
Be aware of the historical context of drug discovery to appreciate modern advancements and regulatory protections.