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Biopharmaceuticals. > Module #3 - SAR > Flashcards

Module #3 - SAR Flashcards

1
Q

what are the 4 types of drug classes

A

enzyme inhibitor
agonist
antagonist
modulator (ion channel agonist/antagonist)

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2
Q

what do the types of drug classes result in?

A

structural effects - usually in some form of shape change that alters the function of the biological target when produces the desired biological response

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3
Q

what types of interactions do drugs use (name and the four types)

A

nonbonding interactions (occurs when drug binds to a biological molecule)
- electrostatics
- hydrogen bonding
- dipole dipole
- van der Waals

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4
Q

how do drugs recognize a biomolecule

A

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

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5
Q

how do drugs bind to molecules covalently

A

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

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6
Q

what are electrostatic interactions (4 things)

A

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

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7
Q

describe the polarity of the binding pocket

A

non polar and lipophilic allowing for strength when outside environment is polar

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8
Q

what are hydrogen bonds (3 things)

A

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)

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9
Q

what are hydrogen bond donors?

A

is what provides the hydrogen in a bond

typically a heteroatom (such as O or N) that has a hydrogen attached

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10
Q

what is a hydrogen bond acceptor

A

provides lone pair to form a hydrogen bond

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11
Q

examples of good hydrogen bond acceptors

A

nitrogen and oxygen

must have lone pair

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12
Q

examples of weak hydrogen bond aceptors

A

sulfur (diffuse electron pairs away)

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13
Q

what are dipole dipole interactions

A

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

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14
Q

what are van Der wall interactions

A

strength increases with larger surface area

helps with de-solvation + drug potency

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15
Q

what is drug potency

A

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

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16
Q

what is lipophilicity

A

decribes how non-polar or greasy a molecule is

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17
Q

what is desolvation

A

removal of a solvent from a material in a solution

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18
Q

describe desolvation

A

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

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19
Q

what is SAR

A

structural activity relationships
process of taking lead molecule, and turning it into a good drug through optimization

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20
Q

general steps of SAR

A

make structural changes to molecule

measure potency

relate the effect to structural change

use information to design next compound to test

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21
Q

what does SPR stand for, and main difference between SPR and SAR

A

structure property relationships

SAR optimizes one drug at a time, SPR optimizes everything at a time

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22
Q

what is the goal of SAR

A

to create a drug like molecule

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23
Q

what are characteristics of drug like molecule

A

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.)

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24
Q

what are common property measurements in SAR

A

solubility
pka
LogP or LogD
molecular weight
permeability
melting point
metabolism
protein binding

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25
Q

what is pKa measurement

A

measures the acid/base nature of a drug

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26
Q

what does LogP/LogD, permeability, and molecular weight assess

A

ability of drug to cross membrane

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27
Q

what does metabolism assess

A

amount of drug entering body and its lifetime in body

28
Q

what doe melting point look into

A

how well drug can get into body and how easy it is to manufacture drug

29
Q

what does protein binding assess

A

amount of drug circulating in body, availability for activity, and lifetime in body

30
Q

why are looking into drug properties important

A

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

31
Q

what do barriers do to drugs in terms of size

A

typically decrease the amount of drug (ex. large amount of drug can enter barrier, only a small amount can come out)

32
Q

how are drugs designed first?

A

as a pill that will go through the digestive system to make its way into the blood stream

33
Q

what is the first barrier in the body + describe characteristics

A

the stomach

very acidic + low in pH (1.4 - 2.1)

34
Q

characteristics of drug to survive in stomach

A

water soluble, and be able to withstand strong acid

35
Q

what is the second barrier in the body + describe characteristics

A

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)

36
Q

what type of diffusion do you want to design a drug for?

A

passive diffusion

37
Q

describe how a drug must pass through intestinal cells

A

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

38
Q

what two simultaneous properties must a drug have to pass through membrane

A

water solubility and lipid solubility

39
Q

what properties can increase/decrease solubility? (to help drug pass outside polar section of bilayer)

A

polar interaction increase solubility:
- electrostatics
-hydrogen bonding
-dipoles

nonpolar interactions decrease solubility
-van der Waals

40
Q

what properties can increase/decrease lipids solubility (to help drug pass through inside non polar section of bilayer)

A

non polar interactions increase lipid solubility:
- van der waals

polar interactions decrease lipid solubility:
- electrostatics
- hydrogen bonding
- dipoles

41
Q

describe characteristics of water environment

A

very polar, hydrophilic, and lipophobic

42
Q

describe characteristics of hydrocarbon environment

A

very non polar, lipophilic, and hydrophobic

43
Q

what quality allows a drug to be both soluble in water (polar) and lipophilic (non polar) regions (ex. to pass through membrane)

A

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

44
Q

how does drug pass through intestinal cell membrane

A

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)

45
Q

what is the third barrier a drug must pass + characteristics

A

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

46
Q

what is the fourth barrier a drug must pass + characteristics

A

blood

mostly water (polar environment)

contains hydrolytic enzymes that are designed to protect body from things in the blood (used to destroy foreign things)

47
Q

what do hydrolytic enzymes in blood do

A

destroy drug molecuels

esterases break ester bonds
proteases break amide bonds

48
Q

what characteristics should drug have to work with blood in body

A

be polar since blood is mostly water (polar) and you want drug to easily dissolve

49
Q

what is the 5th barrier for drugs in body and characteristics

A

kidney

easily clears hydrophilic compounds (polar), but does not easily clear lipophilic molecules (non polar)

50
Q

what characteristics must drugs have to get through kidney barrier

A

find the right balance between hydrophobic/philic and acid base properties

51
Q

what is the 6th barrier for drugs in body and what does it involve

A

target organ

involves passive diffusion from blood to organ

sufficient amount of drug must reach the target to produce a response

52
Q

what properties are associated with ADME

A

absorption
distribution
metabolism
excretion

53
Q

what do larger/small doses entail?

A

smaller = easily get through barriers
larger = hard to get through barriers

54
Q

what is Lipinski’s rule of five general idea

A

way to evaluate drug like properties

predicts poor absorption/permeation

55
Q

what is the actual rules of 5 (criteria)

A

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

56
Q

why is number of H bond donors/acceptors important for drug like properties

A

H bonds increase water solubility/polarity and reduce lipophilicity making it difficult to cross membranes

you need to find the right balance

57
Q

why is molecular weight important for drug like properties

A

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

58
Q

what is LogP and why is it important for drug like properties

A

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

59
Q

formula for LogP

A

LogP = log (solubility in octane/solubility in water) where pH is equal to value that makes molecule neutral

60
Q

formula for logD

A

Log D = log (solubility in octane/solubility in water) where pH is chosen by researcher

61
Q

what pH should be chosen for logD calculations and what should the ideal logD value be in repsonse

A

7.4 should be chosen (biological ph in human body)

ideal logD should be between 1 and 3 at this pH

62
Q

what measurement method is used for logP/logD

A

make standard solution in water

add equal volume of octanol

shake

measure amount of drugs in the two layers

63
Q

advantages/disadvantages of logP

A

A = used by FDA/courts, well established

D: pH will always be different because molecule is neutral, does not reflect biological conditions in body

64
Q

advantages/disadvantages of logD

A

A = easier to measure, correlates to rule of 5, has physiological relevance to biological pH

D = less widely used than logP

65
Q

what does ionization increase

A

water solubility

66
Q

what do neutral forms allow for

A

membrane transit

67
Q

importance of pka

A

if you can tune aka to match ph of a persons body - you can let molecules exist in water and in membranes

Biopharmaceuticals. (5 decks)

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