Irina Lectures

  • Created by: Rscottqub
  • Created on: 28-11-19 12:39
Lead compound
exhibits desired Pharmacological effect but needs to be further developed to optimise bio activity
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5 Natural sources of LCs
1. Plants 2. Animals 3. Marine 4. Venoms and Toxins 5. Microorganisms
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Opium poppy - pain
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pacific yew tree - anticancer
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Fox glove- heart failure
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chinchona tree bark - anti malarial
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periwinkle - anticancer
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How much of plants have been looked at for LCs
0.5% , and yet 25-30% of drugs are from plant sources
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process of screening plants for commercial purposes - in past have used trial and error
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Random screening success rate
1 in 10,000, but if we apply knowledge to this process - increases to 1 in 5000
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Example of marine sources- Erubulin
marine sponge- anti cancer
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puffer fish - neurotoxin - research
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have Marine sources provided many lead compounds
no - many are very toxic - but have use in research
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Screening of microbes has given rise to discovery of
New Antibiotics
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immuno suppressant - prevent organ rejection- isolated from tolycladium
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Ciclosporin is extensively metabolised - how can we slow this?
Grapefruit juice - slows for short time
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Venoms and toxins are used by organisms to ..
protect from predator
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Brazilian pit viper - antihypertensive
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A- bungerarotoxin
bungerous multi- anti cholinergic agent
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Problems with animal sources
ethical issues. limited to in vivo
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Why have few LCs been discovered from animal soruces
similar body chem to humans - few NEW LCs discovered
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Met- enkaphalin
pig brain - analgesic
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frog skin- antimicrobial
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Semi synthesis
chemical manipulation of a natural compound- ie improve stability / toxicity
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Example of s.sythesis
Penicillin G - orally inactive - but on s/synthesis --> formation of new ABs ie amoxicillin
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originates from within an organism
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Modification of existing drugs - me too
drug modified to produce drug with similar properties
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me better drugs
drug modified to produce drug with improved properties
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rational drug design
LC produced from research on disease - design 3D structure of target - synthetic libaries are tested for activity with target
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chance observations and realisation of importance --> produce a LC
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Screening procedure
we must screen for bio activity - both in vivo+vitro test used, we also test for activity at targets other than the desired target to ensure no serious side effects
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In Vitro tests
in Lab , uses ISOLATED enzymes, receptors, cells + tissue etc- we used to get this from animals but now we can use genetic eng
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In Vivo
In body
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Comparison to vitro
more expensive, but easier and faster - in vitro do not guarantee in vivo activity
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What must happen before we can test in vivo
positive result from in vitro- due to cost and ethical issues -
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what type of animals do we use in vivo tests
transgenics are used to test pharmacokinetics
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In order to pick a target what do we need an understanding of
structure of biomacromolecules - to decide if agonist or antagonist should be designed
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In past what used to happen
drug was discovered 1st - and then target found 2nd once drug interacted with it
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Now we ....
have discovered some of the bodys messengers which act on targets , however we still do not know many of them
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Orphan receptors
targets where endogenous messenger is unknown
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substance which prevents/cures disease in animals,plants or humans
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If drugs have similar potency then the more effective is the one ....
with greater selectivity
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Theraputic Index eq
LD50/ED50 LD- toxic dose, ED- effective dose
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5 key properties for selecting a new LC
1. Potency 2. Selectivity 3. Structural novelty 4. Solubility 5. Chemical/Plasma stability
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the amount of drug required to acheive desire pharm. effect. THIS IS THE 1ST SOUGHT PROPERTY OF A LC
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The more drug required
the less potent
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Target specificity
the more selective the drug - the less chance of side effects
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Best targets
are ones which are unique to the particular microbe/tissue - then drug will not interact with other targets - few side effects
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structural variants - diff AA seq/4 structure
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Are receptor agonist/antagonists selective for subtypes of receptor
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These subtypes are located ....
they are not evenly distrubuted around the body- the are conc in places - meaning drug can target specific organs
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Drugs mimiking NT
act more like hormones as have to travel in blood to target, but now can interact with receptors all over body - lots of side effects - ie parkinsons
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often there are multiple enzymes,receptors, messengers involve in a body function- this means there is more than one target ie High BP - CA channel bloc/ACE inhib
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What can happen in a pitfall
drugs designed against a specific target can become less effective over time - and can bypass this part of the system completely to restore to normal
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Structural novelty
1 of 3 requirements to file for a patent . can be most difficult property to fine tune
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is needed for good bioavailabilty
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how to improve solubility
make salt. increase polarity. use produrg. disrupt crystal packing interactions
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Chemical Stability/Plasma stability depends on
Func groups
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Chemical stability
stability in solution at different pHs
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Plasma stability
stability in blood
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Stability will effect
shelf life. in vivo results. ability to survive pH range of the GIT
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Lipinskis Rule of 5
MW < 500. LogP<5 . <10 H bond acceptors . <5 H bond donors
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active confirmation
most drugs can adopt different confirmations - the active one is called the active confrimation
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part of ligand which binds to receptor to produce pharmacological response
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5 Natural sources of LCs


1. Plants 2. Animals 3. Marine 4. Venoms and Toxins 5. Microorganisms

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