Drug Discovery & Development 2 Flashcards
What are the 2 approaches to drug discovery?
Top-down
Bottom-up
What is top-down discovery?
- Candidate drugs screened for effect on phenotype
- Screening on whole animals, organs or cells
- Relevance to disease
- Can only be based on screening for phenotypic changes relevant to treatment of disease
- Biochemical target is identified after phenotypic activity is demonstrated
What is bottom-up discovery?
- Candidate drugs tested for effect on biochemical target molecule
- Testing on biochemical target (receptor, enzyme, DNA etc)
- Defined target for rational drug design
- Can be based on screening of libraries (including natural product extracts) or on structure-based design
- Identification and validation of biochemical target (protein or DNA) is an essential early step
Target based drug discovery route
- Target identification and validation
- Hit generation
- Lead discovery, De novo synthesis
- Lead optimisation
- Pre-clinical tests (animal)
- Clinical trials
- Licensing and marketing
Why does the biochemical target need to be validated?
Validation ensures that, if a drug binds to the target, the desired phenotypic change is achieved
Identification, assessment, validation of the target.
what is the identification process?
- Understanding biochemical pathways
- Understanding signalling pathways
- Understanding expression of genes - profiling
- Data mining
Identification, assessment, validation of the target.
what is the assessment process?
- Drugability
- Availability of structure
- Shape of binding pocket - potency and selectivity
- Selectivity
- Redundancy/duplication
- Does the enzyme catalyse the RDS in a pathway?
Identification, assessment, validation of the target.
what is the validation process?
- Knock-down/knock-out/siRNA
- Knock-in/over expression
- Crude small-molecule inhibitor
What is off-target toxicity?
Toxicity resulting from the drug binding to other protein targets in the cell
Can be addressed by design of drugs which are more selective for the target protein
What is on-target toxicity?
Toxicity resulting from the drug binding to the intended protein target
Unintended consequences
Cannot be addressed by drugs which are more selective for the protein target
What is the next stage of drug discovery after validating the target?
Identifying hit compounds by screening
What does hit compound screening identify?
- Identify hit compounds which bind to the target as inhibitors, agonists or antagonists
- Screen libraries for synthetic compounds
- Screen libraries for natural products
What is HTS?
- High-throughput screening (HTS)
- Automated/robotic up to 10000 compounds d^-1
- HTS assay can be enzyme-activity assay, cellular, spheroids or small organisms
What is MTS?
- Medium-throughput screening
- Automated/manual 10-1000 compounds d^-1
Why design structured compounds of the target?
- 3D structures allow target protein to design ligands
- Fragment based drug discovery
