Module 1: Introduction to Drug Discovery
Explore the stages of the drug discovery pipeline, learn to distinguish key compound classes, and understand how Computer-Aided Drug Design (CADD) accelerates the transition from biological idea to medicine.
1. The Drug Discovery and Development Pipeline
Bringing a new drug to the market is a highly complex, multi-stage, interdisciplinary process. Historically, it requires 10–12 years and upwards of $2.6 billion, with an extremely high rate of attrition. For every 10,000 compounds screened at the outset, typically only one receives regulatory approval.
The pipeline acts as a funnel, filtering compounds through successive hurdles of affinity, selectivity, pharmacokinetics, and safety. Computational chemistry and biology (CADD) have become vital tools to cut costs and time by early filtering and rational design.
Interactive Playground: R&D Funnel Simulation
Click "Advance Pipeline" to simulate compound screening through the five major stages of the drug discovery pipeline. Notice the scale of attrition at each barrier.
10,000 compounds
Ready to begin the R&D pipeline simulations
2. Key Definitions in the Screening Funnel
Hit Compound
A molecule that shows reproducible, verified activity in a bioassay. It must possess validated structure/purity, novelty, and chemical tractability.
Lead Compound
An optimized hit showing activity in vivo, clear Structure-Activity Relationships (SAR), no reactive groups, and clean cardiotoxicity markers.
Drug Candidate
A fully optimized lead structure with robust preclinical safety profiles, ready for Investigational New Drug application and clinical trials.
3. Strategies for Identifying Active Hits
High-Throughput Screening (HTS)
Automated robotic testing of chemical libraries containing millions of synthesized compounds. Highly robust and unbiased, but extremely costly to configure.
Exploitation of Biological Information
Repurposing existing drugs based on unexpected clinical observation of side effects (e.g. sildenafil) or traditional medicine extracts.
Rational Drug Design
Using structural knowledge of the target protein (structure-based) or active ligands (ligand-based) to construct compounds atom-by-atom.
Fragment-Based Screening
Screen very small compounds (< 300 Da) that bind weakly (mM–µM) but with high ligand efficiency. Hits are then grown, linked, or merged into leads. Because fragments are small, a library of a few thousand samples chemical space far more efficiently than a million-compound HTS deck.
DNA-Encoded Libraries (DELs)
Each compound is built by split-and-pool synthesis and tagged with a DNA barcode recording its synthetic history. Billions of compounds can then be screened in a single tube: the pool is washed over immobilized target, non-binders are rinsed away, and the surviving barcodes are read by DNA sequencing. The scale is unmatched — but the readout is enrichment of a barcode, not a clean affinity, and hits must be re-synthesized without their DNA tag to be confirmed. DEL selection data has become a major training set for the machine learning models in Module 9.
4. Targeting the "Undruggable" Proteome
For decades, drug discovery focused on target-based design against deep, well-defined active pockets (e.g. enzyme ATP-binding clefts). However, over 80% of disease-driving proteins lack such cavities, including transcription factors, intrinsically disordered proteins (IDPs), and flat protein-protein interaction (PPI) interfaces.
Once considered "undruggable," breakthroughs in biotechnology and CADD are opening these targets to therapeutic intervention via novel modalities:
Targeted Degradation (PROTACs)
Bifunctional molecules that bind the target protein on one end and recruit an E3 ubiquitin ligase on the other, tagging the target for destruction by the proteasome rather than merely inhibiting it.
PPI Inhibitors & glues
Targeting flat, solvent-exposed protein-protein interfaces. Drugs like Venetoclax target the BCL-2 interface, while molecular glues stabilize target complexes to drive degradation.
Drug Repurposing
Finding new clinical indications for FDA-approved drugs (e.g., sildenafil, aspirin). This bypasses phase I safety barriers, accounting for nearly one-third of recent approvals.