Overview of Drug Discovery and Development Processes

FDA definition of a drug

A substance used in diagnosis, cure, mitigation, treatment, or prevention of disease, affecting body structure/function, excluding food or devices.

General safety rule for drugs

Drugs are considered unsafe until proven safe.

Origins of drugs before the 19th century

Primarily herbal remedies and serendipitous discoveries.

Impact of synthetic organic chemistry on drug discovery

Mid-19th century.

Development characterized the 1920s-30s in drug discovery

Vaccines, vitamins, and the emergence of medicinal chemistry.

Antibiotic Era

1940s.

Major milestone in the 1970s for drug discovery

Rational drug design.

Innovations marked the 1980s-1990s in pharma

Combinatorial chemistry and molecular targeting.

Breakthroughs occurred in the 2000s

Human genome mapping.

Technological advancement impacted the 2010s in drug discovery

Structural biology, computer modeling, and AI.

Drug development pipeline

A multi-phase process involving drug discovery, early development, and full development, typically through academia and pharma/biotech partnerships.

Traditional methods of drug discovery

Serendipity, folk remedies, and natural product extraction.

Examples of drugs from replacement therapy

Insulin and thyroxine.

Rational drug design

Designing drugs based on understanding the biological target and molecular structure.

High throughput screening (HTS)

Automated testing of thousands/millions of compounds to identify potential drugs.

Importance of natural products in drug discovery

They are highly evolved biomolecules with therapeutic potential and biodiversity.

Challenge with natural product drug sources

Access and synthesis can be difficult or impossible.

Example of a natural product drug

Taxol.

Molecular target in pharmacology

A biological molecule that a drug interacts with to exert its effects.

Druggable human proteins

About 3% of 20,000 human proteins.

Potential for antibody binding in human proteins

Approx. 25%.

Percentage of human proteins involved in disease

Around 10%.

Ideal starting point for drug discovery

A validated target with strong disease association.

Examples of strong evidence for a valid drug target

Human genetic mutation, altered gene/protein expression in disease.

Biomarker

A measurable indicator of a biological state or condition related to drug action.

Ligand-based design

Using known ligands to design new drugs through chemical modification and SAR analysis.

SAR

Structure-Activity Relationship.

Pharmacophore

The set of structural features necessary for a drug to interact with a specific target.

Drugs discovered through ligand-based design

Cimetidine (H2 receptor antagonist) and Captopril (ACE inhibitor).

structure-based drug design

3D structure of the target, usually from X-ray crystallography or cryo-EM.

virtual screening in drug design

Using computational models to screen compounds for binding potential.

Lipinski's Rule of Five

Guidelines to assess drug-likeness: MW<500, LogP<5, ≤5 H-bond donors, ≤10 H-bond acceptors.

solubility in a drug

It affects bioavailability and absorption in the body.

bioavailability

The extent and rate at which the active drug enters systemic circulation.

metabolism in drug action

Determines how long a drug stays active in the body.

pharmacodynamics

The study of the biochemical and physiological effects of drugs and their mechanisms.

in vivo profiling

Animal testing to assess drug effects, biomarkers, and pharmacokinetics.

NOAEL

No Observed Adverse Effect Level.

selectivity in drug safety

To avoid off-target effects and toxicity.

hERG

A heart ion channel; drugs must be screened to avoid cardiac arrhythmias.

toxicology testing

Assessment of potential adverse effects of a drug, typically in two animal species.

Warfarin

An anticoagulant that inhibits clotting factor synthesis; dosage is critical.

INR

The rate of blood clotting; used to monitor Warfarin therapy.

biologic drugs

Therapeutics like monoclonal antibodies, proteins, and gene therapies.

drug repurposing

Finding new uses for existing drugs.

phenotypic screening

Testing drugs on cells/tissues to observe physiological responses.

selectivity screening importance

To ensure drugs affect only intended targets and not unrelated systems.

pharmacology in drug development

From screening and profiling to in vitro/in vivo evaluation.

in vitro pharmacological methods

Cell assays, isolated tissues, receptor binding.

in vivo pharmacological methods

Animal models, biomarker evaluation, dose-response studies.

regulatory affairs

Compliance with laws and submitting documentation to health authorities.

medical intelligence support

Gathering scientific and clinical data to support drug development.

Project goals approval in pharma

Management teams with long-term commitments.

Combinatorial chemistry

Technique to create large libraries of molecules by systematic combination.

Benefit of AI in drug discovery

Accelerates prediction of drug-target interactions and structure modeling.

AlphaFold

Predicting 3D structures of proteins to aid drug design.

Antibodies in drug therapy

Targeting specific proteins or cells with high specificity.

Gene therapy

Modifying or replacing defective genes to treat disease.

RNA interference

Silencing specific gene expression to treat disease.

Vaccine mechanism of action

Stimulates immune response to provide protection against pathogens.

Goal of early development in the pipeline

To validate efficacy, pharmacokinetics, and safety in animal models.

Full development process

Human trials (Phase I-III), regulatory approval, and market launch.

Significance of cimetidine

A rationally designed H2 receptor antagonist for peptic ulcers.

SAR in research

Helps researchers determine which chemical modifications improve or reduce biological activity.

Importance of assay development

To reliably measure drug-target interactions and optimize compounds.

Hit in drug discovery

An initial compound with desired activity from screening.

Post-hit identification process

Chemical optimization through medicinal chemistry.

High selectivity importance

Minimizing side effects and increasing drug efficacy.

Genetically modified animals use

To model human diseases and evaluate drug effects.

Knockout model

An animal where a specific gene is disabled to study disease mechanisms.

Good target validation strategy

Using human genetic data, biomarkers, and disease-linked pathways.

Structure-based drug design

Creating drugs that fit precisely into a known target structure.

Cryo-EM and X-ray crystallography

Provide 3D structures of targets at atomic resolution.

Docking in drug design

Predicting how a drug molecule fits into its target's binding site.

pKa effect on drugs

Ionization state, which influences absorption and distribution.

LogP indication

The lipophilicity of a compound; affects membrane permeability.

Characteristics of an ideal drug

Potency, selectivity, solubility, bioavailability, safety.

Importance of antibiotics from natural products

They have complex structures that are difficult to synthesize synthetically.

Challenge of biologics vs small molecules

Complexity of manufacturing, delivery, and stability.

Project team in pharma

A cross-disciplinary group working together on a single drug candidate.

Success measurement in drug discovery

Safe, effective drugs that address unmet medical needs and gain approval.