Drug Discovery 1&2 Flashcards
What are the 3 main sources of drugs?
- Natural compounds
- Small molecules (made synthetically, e.g. Gleevec)
- Recombinant products (i.e. monoclonal antibodies)
How long is the general drugs discovery pipeline?
25
What is IC50?
Te concentration of drug where you get 50% inhibition
What is the typical IC50 of an initial hit in the drug discovery pipeline?
IC50 = 1µM
What is a Hit?
Small molecule with some effect identified by biological and/or computational screening
What is the target?
protein or other molecule whose activity is to modified
What is a lead?
Chemical modification of a hit to enhance its effects and remove adverse effects in ADMET
What is an optimised lead?
- Potency of IC50 <1nM
- Selectivity of 1000 fold compared to similar receptor
- Solubility of <1mg/ml
- ADMET compliancy
- Safety demonstrated in animal
- Efficiency (Better than other drugs) in animal models
What is clinical phase 1?
Small no. of healthy people (20-80) to establish a safe dose
What is clinical phase 2?
Larger numbers of unhealthy patients (100-300) to firm up results from phase 1 and to establish level of effectiveness
What is clinical phase 3?
Thousands of unhealthy patients to prove drug is effective and identify side effects against placebo
What is the regulation phase of the drug discovery pipeline?
Approval for drug to be used and marketed
What is the ‘sales’ phase?
Also known as phase IV - monitoring side effects over years
What is the rough cost of the drug discovery pipeline?
Between $500 million to $1.5 billion
What is attrition rate?
The amount of molecules that are dropped during the drug discovery pipeline
Which is the most expensive phase of the drug discovery pipeline?
Clinical phase 3
What is Eroom’s Law?
The cost per drug production is increasing as efficiency decreases.
What does AMDET stand for?
Absorption Distribution Metabolism Excretion Toxicology
How many drugs is ADMET RESPONSIBLE FOR THE FAILURE OF?
30%
What is pharmacokinetics?
What the body does to the drugs
What is pharmacodynamics?
What does the drug do to the body
What are lipinsky’s rules of 5 for?
Guidelines for a good drug
What are lipinsky’s rules of 5?
- Molecular weight ≤ 500 Da
- Not to lipophilic ClogP ≤ 5.0 (lipophilicity)
- Few H-bond donors (≤ 5)
- Few H-bond acceptors (≤ 10)(sum of Ns and Os)
New additions:
- Number of atoms between 20 and 70
- At least one OH-group
- Less than 8 rotatable bonds
What are the estimated maximum number of drugs that can exist?
10^9-10^13
How many drugs are in circulation?
≤ 1,000,000
What is high throughput screening?
Assaying thousands of drugs for effectiveness.
What are the different plates numbers?
96
384
1536
(or one eppendorf tube)
What is scaffold hopping?
Where you change the structure but maintain the primary chemical features
What is Pharmacophore?
Set of molecular features arranged in relative spatial orientation
What is QSAR?
A quantitative connection between chemical structure and biological activity
What is Ki?
Inhibition constant
What is comfa?
3D QSAR - see condensed notes
What is DUD?
A database of known decoys that allows you to identify decoys in dataset without further experiment
What is an enrichment factor?
A way to evaluate the ability of identifying actives from inactives. % actives in top x%/%non actives/total molecules
What is R.M.S.D?
Deviation from perfect bond angles and bond lengths during docking
What is POSE?
The prediction of how the ligand is orientated in the binding site
How are docking algorithms often characterised?
By the degrees of freedom they acknowledge (DF)
Why in docking aren’t molecules alway considered to be entirely flexible?
This would require a lot of computational time
What is a simple way to identify possible binding sites?
Manually identify large clefts
What would a more complex geometric approach to identifying binding site be?
F-pocket - testing alpha sphere (sphere which can touch at least 4 atoms) that match the size of the ligand to identify possible binding sites
What might be considered in a docking algorithm scoring mechanism ?
Van der waals
Electrostatics
sometimes hydrophobic affect
Some use a softer scoring to prevent omitting potential hit s
What is AutoDock Vina?
It is a simplified scoring model hydrophobic & hydrogen bonding as well steric conditions.
Allows for rotation of bonds in ligand and side chain but not main chain
What is benchmarking virtual screening?
Analysis of whether an algorithm predicts correct POSE and binding site
What is a blind trial?
An interaction that as been determined but not published is tested in the algorithm for it’s accuracy of prediciton
Sicking often fails. Why is it still worth performing?
It is very cheap and quick a large computer farm of 1000 computers can screen 1million molecules in 10 day
