drug design 2 Flashcards
what is lead optimisation
aims to mamimize the interaction of a drug with its rarget binding site in order to improve activity, electivity and to minimize side affects
what does structure based drug design
uses X-ray crystallogrpahy and computer based molecularmodelling to study its binding
how can drug optimaistion be achieved
- variation of sbsituents
-exentision of structure by isosceles and biosteres - simplification of the structure
what si the pharmacetical phase
disintergration and dissolution, determiens amount of drug avalible for absorption
what is the pharamkinetic phase
ADME, deternmines amount of drug avalaible for action
What is the pharamcodynamic phase
interactions with the tissue, dtermines indcution of therpuetic effect, what the drug does to the body
what are examples of enteral routes of administartion
- oral
-retal
-vaginal
what is parental routes of admistration
- intravenous, intramuscular, subcutaneous
if it is oral what do you want the drug to be
inactive so its activited, if its active liver would inactivate
why should you only take one therapy at a time sometimes
the p450 are all occupied
what are dosage form
- lquid formualtuoin
- semisolid formulations
- solid formulations
what is the objective of pharmakinics
optimisation of avalibilty
what factors influecne how drug reaches its target
- hydrophilic/ hydrophobic character (want slighlty more hydrophobic)
- ionisatiobn
- size
chemical and metabolic properties
what are the partition steps drugs will go through
- elave aqueous extracellualr fluid
- passing through lipid membrane
- entering aqueous enviroments before reaching receptor
which enzyme normally breaks down drugs
P450
what are the problems relating to metabolsim
- metabolites have different properties to og drug
- loss of activity
- more toxic
- activity of enzyme varies
what is a pharmacophore
minium structural requirements to have biological activity
what is the role of structure-activity relationship in drug design
changing things like functional groups
what is a drug receprtor
Specialised target macromolecule presnet on the cell surface or intracellularly that binds and mediates is pharmacological action
what are the drug targets
- enzymes
- receptors
- carrier proteins
-structural prtoeins - nucleic acid
- lipids
- carbohydrates
what are agnosists
mimic the chemical messsenger
what are antagonist
- bind to receptor
- dont activate
block binding
what is potentiation
a bigger affect than you would have normally got
what is the most common membrane bound receptor
G- coupled receptors
what are the types f interaction betwen drugs and receptors
- ionic
- h binds
- van der Waal
thsi depends on the fucntion groups and the charges
what allows receptor interactions
- drugs must have correct binding groups
- groups must be corrcetly positioned
- drug needs t be correct size for binding site
what factors influence binding and action
- molecular structure
- isomerism
- fcuntional groups
- rigidity
what is the pharamacophore
- which part of molecular are importat to biological activity
- which functional groups are important to bonding to receptors
what is pharmakinetic optimisation
optimising acess to the target
what is the pharamdynamic optimisation
optimising target interactions
modifciations that affect solubilty
- add ioniazble centre
- increases polaroaty
-decreases lipocicity
modification to permeabilty
- reduces polarity
- increase lipophilicty
- prodrug approaches
what would make a drug cross the blood brian barrier
pro drug approach
increases lipophoicity
what is a pro drug approach
putting the drug as one thing and the it acting as something else
how many rings has morphone got
5
how do you make codine out pf moprphine and whats the difference
reduction in pain relief to 20%
chnage a free hydroxyl group to CH3
how do you have to administer codeine
cannot do if injected stright into CNA, instead need to be oral as needs liver
what happens whern you remove 6OH and replace with acetyl group
get more activity and can pass through to brain at higehr conc as less poalr
what happens whern you remove 6OH and replace with acetyl group
get more activity and can pass through to brain at higehr conc as less poalr
how is diamoprhone (Heriorin) made
take phenol OH and alchohol group and put acteyl groups on and improves blood brain barrier
what is viutal to the pain releif of morphine
nitrogen (ionic bonding)
aramatic ring (van der waals)
phenolic OH (H bond)
the postioning of the drug
what are the most common drug targets
- enzyme
- receptors
what does it mean if a drug is charged
cant travel across membranes
do you want your drug to be slightly hydrophilic or hydrophobic
slighty more hydrophobic
what do the typess of intercations between the drugs and the receptors depend on
fucntional groups
what interctaions might a drug have
- ionic
-ion dipole
-h bonds
what is isomerism
same structure but different arrangemennt
what is an exmaple of ligand based drug design
morphine
how do you look at structure active relationships
take the lead and change its structure
how is codine made from morphone and what is its actitivity
the phenolic OH is replaced with methyl ether and activity is 20% of morphine
how do you increase the potency of morphone and what can it do
swap the 6-OH with 6-acetyl and increases analgesic affects as less polar could potneially move across blood brain barrier
how do you make heriorin from morphine
swap phenolic oh to acetl group as well as 6 OH tho acetyl group get herorin this can cross blood brian barrier and very hydrophobic
what is crucial to analegiscal activity in morphine
the nitrogen and ring, the phenol OH and 6-oh
