Drug Discovery and Development One Flashcards
Whats a general overview of the drug development pathway?
- Early stage research and discovery
- Preclinical studies
- Phase 1-3 clinical studies
- FDA review and approval
What does early stage research and discovery encompass?
- Target ID
- HIT discovery
- Lead Generation
What does target ID involve?
- Phenotypic screen
- HIT discovery
- Target ID
What are two types of screening for drug discovery?
- Target Based (knowledge of drug, choose targets to test)
- Phenotypic (test lots of receptors for effect)
Whats the advantages for target based screening of drugs?
Advantages:
- Application of molecular and chemical knowledge
- Small molecule screening strategy
- Biological development (i.e antibodies)
Whats the disadvantages for target based screening of drugs?
Disadvantages:
- Target might not be relevant to disease
- No therapeutic index
Whats the advantages of phenotypic based screening?
- Does not require knowledge of MOA
- More effective translation from assay to therapeutic impact
What are the disadvantages of phenotypic based screening?
- Optimizing properties with MOA knowledge
- Lower throughput than target based
In target based screening, what are some targets used?
- Ligand binding site
- Catalytic site (enzymes)
- Allosteric site
- Protein-protein interface
- Protein-membrane interactions
In target based screening how do we develop drugs?
- Makes molecules related to the known ligands (analogues)
or
- Screen for knew molecules based on the receptors and known ligand properties
In classical pharmacology, how are receptors classified?
Receptors were classified based on their ligand response profile
(classification could lead directly to new therapies)
Are ligands only recognized by one protein?
Different proteins can recognize the same ligand
Whats an example were drugs were developed based on being analogues to the known ligand?
- Adrenalin acts on adrenoreceptors
- Use antagonism for angina
- Use agonism for asthma
How is angina treated?
Use of propanalol as an antagonist at the b-receptor to decrease its heart rate, thus decreasing the work its performing/oxygen needs
- Doesnt affect contractile state
How are disease states used to develop drugs?
Critical evaluation of disease data generates a hypothesis about what is needed from a drug
What is a HIT discovery?
When the target phenotype is affected by a compound
During the development of propanolol, what pathway of analogues was unsuccessful?
Symmetrical analgoues
What is lead development?
Using a compound that is known to have the same affect (agonist, antagonist etc) as you want, and then looking into analogue structures (produce precise effect)
What was the inertial treatment for asthma?.
Adrenalin
Why was Adrenalin no longer used to treat asthma?
Caused hypertension, tachycardia etc as acted on all receptors
What was the current treatments for asthma based off?
Adrenalin analogues
What must be done in analogue envelopment?
- Toxicity and metabolic profiles must be developed
What is currently used to treat asthma?
Sulbutamol
Why is sulbutamol used?
B2 AR selective Fast Onset Longer acting than isoprenaline Weaker binding Best results by inhalation
Do different agonists stabilize different conformations of the activated receptor-binding pocket?
Protein bind to the ligand i.e protein changes shape not the ligand
Are chemical properties useful in discovery?
Yes, but must refine exactly what you are looking for
How can screening assays be clouded?
Interference of compounds inc:
- Optical interference
- Reactions
- Aggregates
- Pan Assay Interference Compounds (PAIN)
How can you prevent screening assays from being clouded?
- Known problem compounds can be filtered out based on substrucure
When you develop a library of known drug information, whats important about someone using it?
It will be context dependent
i.e Might say a drug doesnt work (but drug was tested under oral admin, when IV it works)
