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biopharm > module 3 > Flashcards

module 3 Flashcards

1
Q

what are 2 ways drugs bind to targets

A
  • non bonding interactions (most common)
  • covalently (determined by non covalent interactions
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2
Q

describe electrostatic interactions

A
  • strongest
  • attraction between +/- charges
  • non directional, strength determined by distance of charges
  • strongest interactions in NON POLAR, HYDROPHOBIC environments
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3
Q

describe hydrogen bonding

A
  • specialized dipole - dipole interactions between slightly positive H attached to heteroatom (N, O) with unpaired electrons of nearby electron donors (N,O)
  • strength depends on distance
  • forces are directional, stronger as X-H bond aligns with orbital holding unpaired electrons
    -stronger interactions in non polar environments
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4
Q

hydrogen bond donors

A
  • NH, OH
  • fgs: OH, NH2, CO2H, CCONHR (AMIDE)
  • C-F (rare) due to high electronegativity
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5
Q

hydrogen bond acceptors

A
  • N, O if lone pare
  • Sulfur (cysteine) RARE
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6
Q

explain dipole-dipole interactions

A
  • attraction between partially positive and partially negative charge
  • result of differences in EN between atoms bonded together
  • slightly positive attracted to slightly negative
  • strength determined by distance
  • non directional
  • stronger in NP/ H-PHOBIC
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7
Q

describe vanderwaals forces

A
  • small, temporary, induced dipole-dipole, relatively weak
  • random movement of electrons creates areas of + and - charge, - - small charges attract or repulse electrons in nearby molecules creating complimentary opposite charges that attract each other
  • non directional
  • stronger interactions with larger contact surface areas b/w molecules
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8
Q

what are examples of strong EWG

A
  • carbonyls
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9
Q

what are features of LDF that make them useful

A
  • create non polar environments

lipophilicity improves potency of drugs:
- de-solvation: minimize h2o interactions
- drug potency/binding: equilibrium between drug dissolved in water and in protein

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10
Q

what is potency

A
  • measure of concentration of drug required to achieve an effect
  • Lowe concentration = high potency
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11
Q

describe de-solvation and why exposed binding sites are weaker than pockets

A

SEE ANSWER

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12
Q

Describe SAR

A
  • structure activity relationships
  • optimize binding
  • structural changes to a molecule
  • MEASURE POTENCY (EFFECT)
  • relate effect to structural change
  • use info to design next compound to test
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13
Q

Describe SPR

A
  • make structural changes to molecule
  • MEASURE VARIOUS PROPERTIES (solubility, stability, hydro, pka, potency, melting point, bioavailability)
  • relate effects to structural change
  • use info to design next compound to test
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14
Q

Describe drug like molecule

A

molecular properties which make drug convenient for patient to use, drugs are use friendly

  1. potent
  2. bioavailable (MOST CHALLENGING)
    - process with properties that work in opposite directions (lipo + hydro)
    - difficult to improve on property without making other worse
  3. chemical behaviour
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15
Q

list common property measurements

A
  • solubility
  • PKa
  • Log P, Log D (lipo in relation ability to cross membrane)
  • molecular weight
  • permeability
  • melting point

LIFETIME IN BODY:
- metabolism (amount entering body, where structure change in FG happens/ or excreted )
- protein binding

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16
Q

what is the target for medicinal chemists

A
  • gastro intestinal tract
  • strongly acidic conditions
  • drugs must be water soluble + survive strong acid
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17
Q

where are most drugs absorbed

A
  • intestinal environment
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18
Q

how are most drugs absorbed

A
  • passive diffusion (95%)
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19
Q

describe diffusion across lipid bilayer + opposite properties

A
  • interior of lipid (hydrocarbon) bilayer is very non polar
  • intermolecular interactions are VDW
  • water soluble to reach bilayer
  • lipid soluble to pass through bilayer
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20
Q

describe the opposite chemical environments

A

water
- very polar medium solvent
- h bonding + dipole interactions
- hydrophilic
- lipophobic

hydrocarbons
- very non polar medium solvent
- VDW
- lipophilic
- hydrophobic

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21
Q

why do negative charges have harder time crossing membrane

A
  • phosphate head that is closer to the membrane is negatively charged
  • repulsion
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22
Q

most drugs are ionizable

A
  • basic: 75% (+)
  • acidic (29%) (-)
  • neutral (5%)
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23
Q

how to create a drug that is ionizable + neutral

A
  • acid base eqiilibirum produces ionized and neutral forms

IONIZED
- acids and bases usually charged at physiological pH making them soluble in water

NEUTRAL
- equilibrium allows them to convert to neutral form to pass through membranes

24
Q

Drugs in the liver

A
  • detoxify
  • metabolism
  • hydrophobic molecules highly metabolized
25
Q

Drugs to the rest of the body by blood

A
  • blood mostly water
  • lipophilic molecules bind to carrier proteins in blood (plasma protein binding)
  • blood contains hydrolytic enzymes (esterase, H2O TO ESTERS, proteases, H2O TO AMIDE)
26
Q

Drugs in kidney

A
  • clears hydrophilic
  • doesn’t clear hydrophobic
27
Q

properties associated with ADME

A

A: absorption
D: distribution
M: metabolism
E: excretion

28
Q

Lipinksis rule of 5

A

if 2 or more: not bioavailable

SHOULD NOT HAVE
- more than 5 h bond donors
- more than 10 h bond acceptors
- molecular weight > 500
- C/ log p > 5, MlogP > 4.15

29
Q

hydrogen bond donors vs acceptors in LIPINSKI

A

donors: h is amount of donors
OH
NH

acceptors: only with lone pair
- N, O

30
Q

rationale for h bonds

A

h bond increase water solubility
difficult to cross membrane

31
Q

rationale for molecular weight

A
  • large molecules less soluble (larger cavity in solvents)
  • do not pass through tightly packed membrane
32
Q

rationale for logP

A

water solubility decreases as lipophilicity increases

33
Q

measurements for lipophilicty

A
  • higher, more lipo

Log P
- drug in neutral form
- log( [drug octanol]/[drug water] )

Log D
- drug in physiological pH
- log( [drug octanol]/[drug water] )

34
Q

advantages + disadvantages of Log P AND Log D

A

SEE ANSWER

35
Q

2 common measurement methods

A
  • solutions (separate layers)
  • HPLC (high performance liquid chromatography)
36
Q

what determines water solubility

A
  • pKa: equilibrium constant related to removal of H
  • ionization increases water solubility
37
Q

pH and pKa

A

molecule is protonated when pH < pKa

pKa range between -1.7 to 15.7
full deprotonated vs protonated

ACIDS
- charged when pH > pKa

BASES
- charged when pH < pKa

38
Q

define amphiprotic

A
  • can acts as base or acid
  • water
  • amines are usually bases, can act as acids but not useful in drug industry
39
Q

pH effects on water and lipid solubility

A
  • solubility in water increases as pH increases, increases hydrophilicity
  • solubility in octane decreases as pH increases, decreases lipophilicity
40
Q

what are the 3 factors that influence drug permeability

A
  • rate at which drug passes through lipid membrane
  • solubility, Log P, molecular weight
41
Q

2 most common assays for permeability

A

Caco-2
- for human colon cancer cells
- at a later stage
- more physiologically relevant, similar to intestinal membrane
- more difficult

PAMPA
- easily done + early stage
- good idea for path diffusion
- no physio relevancy: artificial membrane

42
Q

benchmark values of commercial drugs

A
  • FDA uses BCS: Biopharmaceutical Classification System

Class 1:
- receive waiver for bio equivalence + bio availability studies
- ideal for oral dosing

Class 2:
- permeable but not very soluble
- lipophilic: special formations for solubility

Class 3: soluble but not permeable
- hydrophilic
- pro drugs used to improve permeability

Class 4: low solubility + permeability
- expensive + risky
- used in I.V’s, most cancer drugs

43
Q

Metabolic stability: resistance to chemical change

A

Phase I:
- add polar functional groups to reduce lipophilcity
- oxidation: of aliphatic or aromatic groups: electrons rich sites
- cytochrome P450 (heme iron)
- hydrolysis
- add FG to make more reactive

Phase II:
- conjugation, add groups to improve water solubility
- attach large polar molecule to FG from phase I or already existing
- easier to get make and get rid of hydrophilicity than hydrophobic

44
Q

catalytic cycle of enzyme:

A

see diagram

45
Q

Phase II

A
  • adds polar groups
  • makes it easier for kidney to dispose
  • glucuronic acid, sulfonation, acetylation, glutathione
46
Q

2 common measurements of metabolism

A
  • liver microsomes
  • half-life measured (T1/2)
  • plasma stability (T1/2)
47
Q

process of optimization

A
  • start with lead structure
  • make related compounds
  • change 1 factor at a time
  • measure potency + properties
  • use patterns in data to identify: site on molecule to change/not change, good/bad modification
48
Q

techniques of molecular modification

A
  • addition/deletion
  • substitution
  • chain extension/contraction
  • ring expansion/contraction
  • ring variations
  • simplification
  • rigidification
49
Q

describe substitution + use of isosteres

A
  • replace FGS
  • groups of similar steric + electronics
  • similar bio activity
  • similar shapes/size
50
Q

describe classical isosteres

A
  • atoms or groups with same valency and similar size
  • help determine if groups important for binding or not
  • very controlled
  • same group on periodic table
    OH –> F, Cl, SH, NH2, CH3

SEE EXAMPLES

51
Q

describe non classical isosceles (bioisosteres)

A
  • atoms or groups with similar chemical properties
  • differ in electronics + steric
  • can enhance metabolic stability, reduce side effects, etc

SEE EXAMPLES: tetrazole

52
Q

describe chain extension/contraction

A
  • better alignment and better binding to binding site
  • SEE DIAGRAM
53
Q

describe ring expansion and contraction

A
  • can use heteroatoms
  • SEE DIAGRAM
54
Q

describe structure simplification

A
  • remove parts that do not affect potency
  • remove stereocenters
  • take into account spacing for proper alignment
  • SEE DIAGRAM
55
Q

stereocenters and racemates

A
  • avoid sterecenters: difficult to manufacture + extra testing
  • racemate: easier to make + test, test both conifgurations
  • test enantiomers as diff compounds BECAUSE THEY SHOW DIFFERENT PROPERTIES
56
Q

describe pharmacophore

A
  • groups that are important for activity, part that is responsible for activity

biopharm (4 decks)

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