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
What are the pros and cons of peptide drug design?
pros - High selectivity - High potency - Low toxicity - If small can be cheap - Easy to modify Cons - poor pharmacokinetics - risk of immune system reaction - hard to administer - if big then expensive
What things are looked for in cell based assays?
Further biochemical verification – search for biomarkers, functional changes, detailed signalling modifications
Which techniques can be used for cell based assays?
Extraction of DNA, RNA, proteins, lipids, and detailed image analysis
What are the advantages of cell based assays?
- Increase in complexity from high throughput assays
- Amenable to a large number of research techniques allowing detailed image analysis
- Cheaper and more ethical than animal models (however some cell cultures are expensive e.g neurons)
What are the use of animal models in drug testing?
- See how drug functions in complex mammalian system (however increasing use of drosophila and c elegans)
- Absolute requirement of drug development
- However must be refined as much as possible beforehand to minimise use
- Limited research techniques available but can be precisely targetted
Describe phase 1 trials?
- Prior to them beginning all data examined
- small group of healthy volunteers (young men)
- Look for any side effects, tolerability, pharmokinetics (drug excreted/metabolised) and carrying out of experiments
Describe phase 2 trials?
- Small group of people with target disease at the same level of progression, dose response experiments to calculate optimal dose in humans
- First indication of whether drug will work for someone’s condition
- Monitor disease progression and efficacy in small population before moving to multi-centre trials (Usually not successful)
Give an example of an unsuccesful phase 1 trial
Northwick park drug trial for leukemia and rhumatoid arthiritis drug - All developed severe side-effects - Cytokine storm induced, patients loosing parts of fingers and now a huge increase in their own cancer risk
Give an example of an unsuccesful phase 2 trial
- Tirasemtiv is an orally bioavailable molecule that sensitizes the troponin complex in fast-twitch skeletal muscle fibers to calcium, could be used to treat ALS - Was negative on a functional scale but did increase muscle strength - Was discontinued but possibility that it could work at a different point in the progression of the disease or given for longer
What are phase 3 trials?
- Double blind and requiring thousands of participants
- Pharmoeconomic analysis (is this cost effective?)
- Expensive and labour intensive
What are phase 4 trials?
- Post marketing monitoring
- Looking for rare side effects or long term effects
- May restrict group to who it is available (e.g women and children) as drugs can act differently at different times in life
What is tetratology?
study of abnormal development and the causes of congenital malformations
What is a teratrogen?
an agent that induces congenital malformations
When is a fetus most vunerable to teratogens?
3 weeks - nervous system and heart are developing which are vunerable 3-9 weeks - critical period where teratogens can have debilitating and life threatening effects
What two ways can drugs given to a mother affect a baby?
- Through breastmilk - Through embreyonic development
What are the functions of the placenta?
- Gaseous exchange - Nutrient supply - Removal of waste products - Active transport of maternal antibodies - Hormone production to maintain pregnancy
What factors affect differences between how a drug may behave in a mother and fetus?
- Placenta may change drug confirmation - Fetus has no fat stores and therefore different pharmacokinetics as drugs cannot accumulate in fat - More cell division - Critical periods of cell death for patterning - Placenta is not uniform can be diffuse membrane or zonal
How may teratogens be studied?
FETAX system - use of frog embreyos, are quick to develop (3 days) and so therefore can conduct many tests however do not show placental effects
