Drug Discovery and development Flashcards
What is High throughput screening (HTS)?
A method that involves using a biological assay to identify mechanisms of action without knowing the structure.Puts different structures with the drug target and uses an assay to test if novel molecules bind to the target
What is a compound library
A collection of structures that can be used in High throughput screening. A good library is full of representative compounds (not just series molecules), and lead like (follow RO5)
What is the Lipinski Rule of 5
Desirable properties for an orally active drug MW < 500 LogP < 5 HBD < 5 HBA <10
What is the process of rational drug design
Generate a model of the target receptor/enzyme.Use this to build the drug to fit the gap.
However, doesn’t always work because proteins are flexible, and this doesn’t account for induced fits
Why is the HERG channel important in drug design?
Drugs that block the HERG channel can cause ‘Torsades de Pointe’, a drug induced arrhythmia. This can cause death by ventricular fibrillation.
How was the drug ‘Maraviroc’ developed?
It is a GPCR (CCR5) antagonist (Go/Gi coupled).
CCR5 cell line used with a displacement assay to find a suitable molecule.
First molecule was an agonist, so structure changed so drug was viable with no side-effects.
Improved structure was sent to other drug companies to test against their compound libraries, and was deemed safe.
Tested in animals, and gave good results. TAH DAH!
What are the stages involved in drug development
Preclinical/clinical development.
Registration
Marketing and sales
What are the advantages of fragment screening?
Smaller libraries cover large chemical spacePotential to produce better fitting compounds
What are the disadvantages of fragment screening?
Crystalline structure requiredSpecific/specialised assay technology used
What is the role of DMPK in drug discovery
Potential drugs are selected with DMPK properties appropriate to the intended drug target
What are the most commonly targeted molecules
GPCRs Ligand gated ion channels Nuclear receptors EC2 transferases Ion channels
What does the process of highthroughput screening involve
Test compound library
Retest positives (to weed out false positives)
Assess responses at different concentrations
Purify compounds and assess
TAH DAH! confirmed hit compounds
What is lead optimisation
Transforming a biologically active compound into a clinical candidate. Involves optimising good bits, confirming activity in model organism and reducing side effects
What are the 4 phases of lead optimisation
1a - activity/solubility/selectivity
1b - in vitro ADME
2 - in vivo ADME/activity
3 - safety
How is drug metabolism tested in vitro (model)
Liver microsomes (contains phase 1 and 2 enzymes; requires co-factor supplements) Liver hepatocytes (expensive)
What are the desired properties of a fragment for use in fragment screening
Rule of 3:
MW
What is ligand efficiency
LE = [change in Gibbs] / [number of non-hydrogen atoms]
or
LE = 1.4(-Ln IC50)/ [number of non-hydrogen atoms]
What are the pros of fragment screening
Smaller library; large chemical space
Could produce better fitting compounds with more effective binding
Better starting point for DD
What are the cons of fragment screening
Fragments have low potency
Specific/specialised assay needed
Crystal structure needed
What are the stages involved in Drug Discovery
Target discovery
Lead discovery
Lead optimisation
Pre-clinical / clinical development (stage 1-2a)
How is teratogenicity tested for in vivo and what are the limitations
Animal studies. Daily dosage during early stages of pregnancy. Assess any abnormalities that occur.
Limitations:
Time consuming, species differences, developmental differences, nutrition
How is teratogenicity tested for in vitro and what are the limitations
Embryo culture/stem cells used in toxicity assays.
Limitations:
False +/- ves. Drug may be metabolised to a tetragen in vitro. PK may exclude embryo from exposure to toxic concentration
What happens in phase 1 clinical trials
Safety and tolerance tests (MTD, etc)
50-100 volunteers
PK/PD + dosage studies
What happens in phase 2 clinical trials
Dose-efficacy relationship (IC50, EC50, MTD/C etc)
400-800 patients
What happens in phase 3 clinical trials
Two successful trials required for marketing approval.
Large patient group - 300-3000
Measures efficacy in target indication (double blind randomised trials, placebo/active controls)
Establishes long term safety/efficacy
What happens in the approval/registration phase of Drug development
Data collected to make a regulatory submission document (animal/human, safety, etc)
Approval time ~ 18 months…….. (FDA, EMEA, etc)
What happens in phase 4 clinical trials
Monitoring efficacy and costing. Identify other uses for drug/ side effects etc.
May cause market withdrawal or restrictions
Define biomarker
A biochemical feature/process that can be used to measure the progress of a disease or the effects of a treatment using non-invasive procedures
Define translational biomarker
Common biological/biochemical measures that can be made in animals and humans. Useful to test efficacy, PK, safety.
How can translational biomarkers be applied to clinical development
Can be used in phase 0 trials (10-15 patients, sub-therapeutic dosage, Pk/PD relationships noted, to confirm predictions). Will give a go/nogo decision early on. Non-invasive.
How might biomarkers be used in the future
Could be used to determine personalised medicine (e.g. breast cancer: ER +ve, HER2 overexp, BRCA1/2 mutation).
