Theme 3 Lecture 9 Flashcards
Diseases that have not been found out to be controlled via drug discovery
Cancer, inflammatory diseases, world diseases (malaria) and neurodegenerative diseases like dementia.
What are the phases of drug discovery and development?
Target selection Phase 0
Hit identification Phase 1
Lead identification Phase 2a
Lead optimisation Phase 2b
Candidate Drug Nomination Phase 3 and launch
Pre-clinical development Phase 4
How are chemical starting points found? (5)
Natural products
High Throughput screening
Fragment-based drug discovery
Virtual screening
Fast-follower approaches
HTS explained (DMSO)+IC50
Screen millions of compounds which are owned by the big pharma companies.
An IC50 derived from a dose-response using a HTS assay on a sample solution in dimethyl sulfoxide (DMSO).
Fragment based screening
Low molecular weight compounds are screened.
Relies on NMR, X-ray crystallography and NPA screening.
Virtual screening SBD and KBD
3
Have the concept of the 3 point pharmacophore model.
Structure based drug design and Knowledge based drug design.
This leads to new HITS.
Fast follower method (clinically validated receptor)NO new ligands
Designing a new drug that is already active at a clinically validated receptor.
Not trying to discover new ligands, more different derivatives of the drug.
Why is the drug discovery process broken down into specific areas?
To allow progress review and set goals for each stage. Ensures the project meets deadlines before advancing and allows comprehensive evaluation for decision-making. A successful outcome may include terminating or parking a project.
How does fragment-based drug discovery (FBS) differ from conventional high throughput screening (HTS), and what are their benefits and limitations?
HTS screens large numbers (>100,000) of compounds, detecting activity in the 1–20 μM range without needing an isolated protein target, but often results in many false positives.
FBS screens fewer, lower molecular weight compounds, detecting direct binding even at high concentrations with fewer false positives. However, evolving FBS hits to high-potency leads can require significant effort.
Difference Between a Hit and a Lead Compound
A hit is a compound with defined structure and biological activity at a certain threshold. A lead, usually derived from optimizing a hit’s properties, has the potential to become a drug candidate.
Selectivity, potency and pharmaceutical properties are looked for in the lead compound
Biological assays in modern day drug discovery
They must be robust (accurate and repeatable) in measuring biological activity in a biological system and reproducible
Reading off an assay graph
Those with the highest inhibition will be further along the bottom axis.
What are the 4 different types of assays?
Enzymatic or biochemical assays
Binding assays
Functional assays
Phenotypical assays
Enzymatic or biochemical assays:
Assay measures the activation or inhibition of the product that is formed.
Problem is it doesn’t measure toxicity or cell permeability.
How can we measure the inhibition of protease activity in a biological sample?
Use a fluorogenic substrate (FRET) designed to be recognized and cleaved by the target protease. Upon cleavage by the protease, a fluorescent dye is released, emitting a detectable signal.
The level of fluorescence corresponds to the protease activity, allowing for the quantification of protease inhibition based on the reduction of the fluorescent signal.
The degree of inhibition leads to the amount of fluorophore released
