Definition of a drug?
An active ingredient that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, treatment or prevention of a disease.
Or to effect the structure or any function of the human body, but does not include the intermediates used in the synthesis of such ingredients.
Lipinskin rule of 5 for the physiochemical properties for an orally active drug?
- Molecular weight <500
- lop5 <5
- Number of hydrogen bond donors <5
- Number of hydrgoen bond acceptors <10
Additional considerations for the physiochemical properties for an orally active drug?
- Number of aromatic groups
- Number of rotatable bonds
- Polar surface area
- Presence of known toxic groups
Physiochemical properties for an orally active drug?
Drugs have basic physiochemical proporties
Keeps the drug safe
The drug discovery and development process?
Name the 5 ways to screen for drug discovery?
- Identify a target implemented in disease.
- Identification of chemical starting points for drug discovery.
- Looking for validated hit series which modulates target or cell type of interest.
- Optimisation of compounds to deliver properties suitable for study in animal models of disease.
- Develop drugs with the appropriate activity and safety for clinical development
Name the 3 tools used for modern drug discovery?
- Recombinant proteins (prified or recombinant cell lines)
- Large compound libraries
- High throughput screening technologies
High throughput screening (HTS)
Screen different compounds to see what they do to the receptor.
Binds to the receptor and activates it causes a response
Binds to the same site as agonist
Blocks the site for agonist so they cannot cause a response.
Posiive allosteric modulator?
Increase the response
Negative allosteric modulators?
Decreases the response.
Binds to another site of the receptor away from the agonist/antagonist
HTS approach to HIT identifiactions
A large library of compounds.
Screen each compound for their effect on the drug target.
Might have low affinity or potency etc- need to optimise them
Name the 4 things that are screened?
- Start points for drug discovery
- Repurpose drugs
- Produce tool molecules (finding a function for unknown proteins)
- Demonstrate ligandability of large.
What are the sources that are screen for a chemical starting points?
Look at existing drugs
Then expand the search more looking and endogenous ligands and natural products.
Eventually, if a compound is still not found will look at rational design compounds.
Look at a small library first of compounds that should work and eventually will get bigger as the search expands
What is the typical number of compounds screened?
100,00 to 1,000,000.
What is the chemical space defined as?
All the possible combinations of possible drug molecules
What must you have in a library of compounds?
A large and diverse library with a range across the chemical space.
How are the compounds of the library stored?
they are stored at a cool temp to stop them from degrading
Compound library design
- Quality of library is essential
- Representative compounds with potential for optimisation.
- New compounds set to design to 'lead-like' properties
6 of them
- Molecular weight 180-350
- lopP about 1-3
- Number rotatable bonds <7
- Number of hydrogen bonds donors <3
- Number of hydrgoen bond acceptors <8
- No structural alert
Keep library small but diverse so you can screen them quickly.
Screening of well characterised proteins (most drugs come from a limited set of protein families)
Structure based drug discovery
Linking of target families
Expressed like a phyletic tree.
Particular chemical families- similar sequences
Most drugs come for the same group(s) of families
Model of target receptor/enzyme
Either via direct crystal structure or indirect homology model.
Name the two rational designs?
- Compound screening
- Hit and lead optimisation
Applications of rationale drug design?
- Useful in conjunction with fragment and focused screening
- Useful for refining activity of existing ligand series
- Crystallography may provide information about mechanism of action
Why cant we design a drug around the shape of the receptor
Using rational design
It is only a single representation of one confirmation therefore does not account for induced fits
Fragments have a molecular weight of 100-250
More efficient binding.
Small library but covers a larger chemical space.
Fragment screening must follow what rule?
What does this rule say?
Rule of 3.
- MW <300
- Hydrogen donors <3
- No. Rotatable bonds <3
What is the negatives of fragment screening?
Could have low potency
Must measure ligand efficiency
Ligand efficiency equation?
What does ligand efficiency tell us?
To determine the potency.
Clincically used drugs are usually more potent to decrease the dose needed
What are the limiations to fragment screening?
Need crystal structure
Need soluble protein
What are the positives and negatives of using fragment screening?
Smaller libraries cover larger chemical spaces
potential to produce better fitting compounds
Better starting point
Fragments have low potency
Need crystal structure
Two specific technologies used to screen assays?
Automated compound handling
Optical readers for plate based assays
Typical screening assays for GPCRs
Radioligand binding assays
Displacement assay- competitive ligands
GTPS assay- agonist/inverse agonist
agonist can increase the S to GTP binding.
Antagonist decrease agonist stimulated S binding
Agonist stimulation modulated by PAMs and NAMs
Calcium sensitive dyes?
Used in functional cell based assay
Alpha screen assay?
Using florescent light
Agonist elicited recruitment of beta-arrestin.
Catalytic conversion of substrate to a chemiluminescent product
2 ways to screen for biased GPCR ligands?
G protein mediated
Equation used by the surface plasmon resonance for fragment screening
The equation used by the isothermal titration calorimetry for fragment screening?
The two calculations for ligand efficiency?
R: gas constant; t: Absolute temp; N: no. non-hydrogen atoms
The dissociation constant.
Synthesis and test a small number of hit analogues
Determine priniciple liabilities for each hit series.
Focussed SAR campaigne
Transform biologically active compound into clinical drug
What must the drug be optimised to prevent?
Survive a range of pH (1.5- 8)
Survive intetsinal flora
Survive liver metabolism
Avoid active transport to bile
Avoid excretion by kidneys
Role of DMPK?
To promote the rapid selection and progression of compounds with human DMPK propoerties
Active (linked to ATP) or secondary active (linked to electrochemical gradient)