Drug Discovery and Drug Design Flashcards
What are all the steps in the drug discovery process?
- Target identification - Target assay construction/screening - Target validation/medicinal chemistry safety - Phase 1 testing: safety - Phase 2: safety and efficacy - Phase 3: large scale - Phase 4: FDA review and approval
Name all the different ways in which a drug may be discovered
- Screening compound libraries - Serendipity - Improvements on current drugs - Farming existing knowledge from other cultures - Targeted drug design - Redeployment of existing drugs for new purposes - From receptor theories
What are the criteria for screening compound libraries?
- Must know what receptor is - Obtain compound library via commercial route or drug discovery unit - Effective moeitys but also ‘space fillers’ available - Ideally need a high throughput assay
What can be looked for when screening a compound library?
- Downstream signalling, activation of second messengers - Enzyme activity (e.g a fluorescent substrate used) - Calcium influx (can read influx)
What is the output from screening compound libraries?
- Initial screens look for ativation of receptor/signalling cascades to identify ‘hit’ molecules - Further develop hits in order to refine the molecule
What are the advantages and disadvantages of screening compound libraries?
Adv - Rapid and wide reaching - Require little technical expertise Disadv - Requires careful analysis - Many compounds are unsuitable to be drugs - Can be cheap but also very expensive
Give an example of a serendipitous drug discovery
Penicillin is derived from a mold (staphylococcus) found growing on cell culture plates, observed to have antibiotic properties by Flemming
What is pharmacology through farming knowledge?
- Through listening to local remedies by other cultures - May be looking at synergistic effect of multiple drugs - Fractions can then be extracted and activity determined
What are the pros and cons of farming knowledge?
Pros - All cultures have traditional remedies - Types of disease targeted are known - Good patient perception - Environmental and economic benefits Cons - Fear that globilization is ‘diluting’ tradition - Receptor is likely unknown - Costs to produce pure drug can be high
What is targetted drug design?
Where both the receptor and endogenous ligand are known and so the receptor is targeted through the addition/blocking of the ligand - Can we modify ligand into drugable compound? (PROTEIN BASED THERAPEUTICS)
What are the pros and cons of targeted drug design (specifically protein based therapies)?
Pros - We know a lot about proteins and they are well tolerated Cons - Hard to administer - Rapid in vivo degradation - May be immunogenic - Expensive and difficult to manufacture
What are the effects of leptin as a drug against Alzheimers disease?
- Prevents detrimental effects of of beta amyloid on hippocampal LTP - Prevents beta amyloid mediated cell death - Prevents beta amyloid from upregulating the phosphorylation of tau - Leptin insensitivity causes phospho-tau upregulation in vivo
What are the advantages and disadvantages of leptin as a drug?
Pros - Counteracts AD at multiple levels - Already licensed to treat obesity - Well tolerated by the body (already made as a hormone) Cons - Large and expensive molecule (however activity now found to only require 15 proteins!) - Hard to administer
How may protein drug compounds be stabilised?
- Modelling and synthesis of synthetic peptides to then conduct peptide-protein studies - Halgoenated peptides are much more stable and bromine can sometimes cross blood-brain barrier - Also can cyclise by joining side chains/amino group/carboxyl group. This provides resistance to proteolysis but can restrict the degrees of freedom and so decrease binding specificity to receptors
What is sequence modification?
Natural - enhancing potency of interaction of protein with receptor by a few changes Unnatural - designed to introduce new functionalities with potential beneficial effects
