Module #3 - SAR Flashcards
what are the 4 types of drug classes
enzyme inhibitor
agonist
antagonist
modulator (ion channel agonist/antagonist)
what do the types of drug classes result in?
structural effects - usually in some form of shape change that alters the function of the biological target when produces the desired biological response
what types of interactions do drugs use (name and the four types)
nonbonding interactions (occurs when drug binds to a biological molecule)
- electrostatics
- hydrogen bonding
- dipole dipole
- van der Waals
how do drugs recognize a biomolecule
by recognizing its pattern of non-covalent interactions (molecular recognition)
pattern of non-covalent interactions on a drug must match up with non covalent interactions on a biological molecule in order for drug to stick
how do drugs bind to molecules covalently
first recognizing a drug with same pattern of NC interaction
two functional groups on the two molecules can then come together and form a covalent interaction
what are electrostatic interactions (4 things)
full positive charge attracted to fiull negative charge
stronger in non-polar environments than in polar environment
closer together = stronger interaction
nondirectional: meaning that it doesn’t matter what way the charges are pointing, or how the groups are lined uup
describe the polarity of the binding pocket
non polar and lipophilic allowing for strength when outside environment is polar
what are hydrogen bonds (3 things)
hydrogen on a heteroatom (usually N or O) becomes positive ad attracted to a pair of electrons on a nearby atom forming a bond
polar interaction, so gets stronger in non polar environments and weaker in polar areas
is directional = strongest when X-H bond points towards the axis of lone pair acceptor (everything is in a line)
what are hydrogen bond donors?
is what provides the hydrogen in a bond
typically a heteroatom (such as O or N) that has a hydrogen attached
what is a hydrogen bond acceptor
provides lone pair to form a hydrogen bond
examples of good hydrogen bond acceptors
nitrogen and oxygen
must have lone pair
examples of weak hydrogen bond aceptors
sulfur (diffuse electron pairs away)
what are dipole dipole interactions
stronger interaction in non-polar environments because polar interaction
dipole get sets up through a bond formed from the negative end of a polar molecule and the positive end of another polar molecule
what are van Der wall interactions
strength increases with larger surface area
helps with de-solvation + drug potency
what is drug potency
an equilibrium between drug dissolved in water and drug dissolved in protein
low concentration = high potency = tighter drug sticks to target
measures concentration of drug required to achieve effect
how well drug sticks to target
what is lipophilicity
decribes how non-polar or greasy a molecule is
what is desolvation
removal of a solvent from a material in a solution
describe desolvation
binding pockets are full of water
water molecule are stripped away as drug enters binding site
drugs and binding pockets often lipophilic which helps with water removal
water removal allows for drug to stick to target
what is SAR
structural activity relationships
process of taking lead molecule, and turning it into a good drug through optimization
general steps of SAR
make structural changes to molecule
measure potency
relate the effect to structural change
use information to design next compound to test
what does SPR stand for, and main difference between SPR and SAR
structure property relationships
SAR optimizes one drug at a time, SPR optimizes everything at a time
what is the goal of SAR
to create a drug like molecule
what are characteristics of drug like molecule
potent (small dose for desired effect)
bioavailable (drug enters blood stream after dosing - can get into a persons body)
good chemical behaviour (easy to make, stable, easy to store, doesn’t have to be refrigerated, etc.)
what are common property measurements in SAR
solubility
pka
LogP or LogD
molecular weight
permeability
melting point
metabolism
protein binding
what is pKa measurement
measures the acid/base nature of a drug
what does LogP/LogD, permeability, and molecular weight assess
ability of drug to cross membrane
what does metabolism assess
amount of drug entering body and its lifetime in body
what doe melting point look into
how well drug can get into body and how easy it is to manufacture drug
what does protein binding assess
amount of drug circulating in body, availability for activity, and lifetime in body
why are looking into drug properties important
before a drug can bind to its target, it has to enter the body and pass chemical barriers
chemical properties control how easily a drug passes barriers
properties must be optimized for drug to get into body
what do barriers do to drugs in terms of size
typically decrease the amount of drug (ex. large amount of drug can enter barrier, only a small amount can come out)
how are drugs designed first?
as a pill that will go through the digestive system to make its way into the blood stream
what is the first barrier in the body + describe characteristics
the stomach
very acidic + low in pH (1.4 - 2.1)
characteristics of drug to survive in stomach
water soluble, and be able to withstand strong acid
what is the second barrier in the body + describe characteristics
intestine
mildly abiding (mostly basic) to neutral pH (4.4 to 6.8)
contain bile salts that solubilize lipophilic salts
is where drugs are usually absorbed (by entering intestinal epithelial cell)
what type of diffusion do you want to design a drug for?
passive diffusion
describe how a drug must pass through intestinal cells
outside of membrane is polar (water and phospholipid heads), and inside of membrane is non-polar (fatty acid chains)
drug must then be able to pass from water to lipophilic environment to water again
therefore, drug must have simultaneous properties
what two simultaneous properties must a drug have to pass through membrane
water solubility and lipid solubility
what properties can increase/decrease solubility? (to help drug pass outside polar section of bilayer)
polar interaction increase solubility:
- electrostatics
-hydrogen bonding
-dipoles
nonpolar interactions decrease solubility
-van der Waals
what properties can increase/decrease lipids solubility (to help drug pass through inside non polar section of bilayer)
non polar interactions increase lipid solubility:
- van der waals
polar interactions decrease lipid solubility:
- electrostatics
- hydrogen bonding
- dipoles
describe characteristics of water environment
very polar, hydrophilic, and lipophobic
describe characteristics of hydrocarbon environment
very non polar, lipophilic, and hydrophobic
what quality allows a drug to be both soluble in water (polar) and lipophilic (non polar) regions (ex. to pass through membrane)
be ionizable (having acid/base properties)
–> 75% are basic and positive at physiological pH value
–> 20% are acidic and negative at physiological pH value
–> 5% are neutral
how does drug pass through intestinal cell membrane
uses acid base properties
starts off charged (either positive or negative)
becomes neutral inside the membrane
charge returns (either positive or negative) once it exits membrane by managing pKa (you want pKa in range of 7.4 to correspond with body)
what is the third barrier a drug must pass + characteristics
the liver
designed to protect us from toxins + chemical metabolizes/changes structure of things to make it not toxic + easily removed from body
recognizes non polar stuff as toxic and changes into polar material
what is the fourth barrier a drug must pass + characteristics
blood
mostly water (polar environment)
contains hydrolytic enzymes that are designed to protect body from things in the blood (used to destroy foreign things)
what do hydrolytic enzymes in blood do
destroy drug molecuels
esterases break ester bonds
proteases break amide bonds
what characteristics should drug have to work with blood in body
be polar since blood is mostly water (polar) and you want drug to easily dissolve
what is the 5th barrier for drugs in body and characteristics
kidney
easily clears hydrophilic compounds (polar), but does not easily clear lipophilic molecules (non polar)
what characteristics must drugs have to get through kidney barrier
find the right balance between hydrophobic/philic and acid base properties
what is the 6th barrier for drugs in body and what does it involve
target organ
involves passive diffusion from blood to organ
sufficient amount of drug must reach the target to produce a response
what properties are associated with ADME
absorption
distribution
metabolism
excretion
what do larger/small doses entail?
smaller = easily get through barriers
larger = hard to get through barriers
what is Lipinski’s rule of five general idea
way to evaluate drug like properties
predicts poor absorption/permeation
what is the actual rules of 5 (criteria)
compounds that meet 2 or more of criteria not likely to be well absorbed by body:
- more than 5 H bond donors
- more than 10 H bond acceptors
- molecular weight greater than 5000
- calculated LogP(CLogP) greater than % or measured LogP greater than 4.15
why is number of H bond donors/acceptors important for drug like properties
H bonds increase water solubility/polarity and reduce lipophilicity making it difficult to cross membranes
you need to find the right balance
why is molecular weight important for drug like properties
large molecules are less soluble + small molecules are more soluble in water
larger molecules difficult to dissolve in solutions
larger molecules also do not pass through tightly packed lipid areas of membranes
have to find right balance for dissolvation to occur
what is LogP and why is it important for drug like properties
LogP is a measurement of lipophilicity
if high logP = too lipophilic = does not dissolve in water (polar areas)
if low logP = is hydrophilic = does not dissolve in membrane
must have right balance between the two properties
formula for LogP
LogP = log (solubility in octane/solubility in water) where pH is equal to value that makes molecule neutral
formula for logD
Log D = log (solubility in octane/solubility in water) where pH is chosen by researcher
what pH should be chosen for logD calculations and what should the ideal logD value be in repsonse
7.4 should be chosen (biological ph in human body)
ideal logD should be between 1 and 3 at this pH
what measurement method is used for logP/logD
make standard solution in water
add equal volume of octanol
shake
measure amount of drugs in the two layers
advantages/disadvantages of logP
A = used by FDA/courts, well established
D: pH will always be different because molecule is neutral, does not reflect biological conditions in body
advantages/disadvantages of logD
A = easier to measure, correlates to rule of 5, has physiological relevance to biological pH
D = less widely used than logP
what does ionization increase
water solubility
what do neutral forms allow for
membrane transit
importance of pka
if you can tune aka to match ph of a persons body - you can let molecules exist in water and in membranes
