1
Q
what are 2 ways drugs bind to targets
A
- non bonding interactions (most common)
- covalently (determined by non covalent interactions
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
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
4
Q
hydrogen bond donors
A
- NH, OH
- fgs: OH, NH2, CO2H, CCONHR (AMIDE)
- C-F (rare) due to high electronegativity
5
Q
hydrogen bond acceptors
A
- N, O if lone pare
- Sulfur (cysteine) RARE
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
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
8
Q
what are examples of strong EWG
A
- carbonyls
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
10
Q
what is potency
A
- measure of concentration of drug required to achieve an effect
- Lowe concentration = high potency
11
Q
describe de-solvation and why exposed binding sites are weaker than pockets
A
SEE ANSWER
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
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
14
Q
Describe drug like molecule
A
molecular properties which make drug convenient for patient to use, drugs are use friendly
- potent
- bioavailable (MOST CHALLENGING)
- process with properties that work in opposite directions (lipo + hydro)
- difficult to improve on property without making other worse - chemical behaviour
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
16
Q
what is the target for medicinal chemists
A
- gastro intestinal tract
- strongly acidic conditions
- drugs must be water soluble + survive strong acid
17
Q
where are most drugs absorbed
A
- intestinal environment
18
Q
how are most drugs absorbed
A
- passive diffusion (95%)
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
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
21
Q
why do negative charges have harder time crossing membrane
A
- phosphate head that is closer to the membrane is negatively charged
- repulsion
22
Q
most drugs are ionizable
A
- basic: 75% (+)
- acidic (29%) (-)
- neutral (5%)
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
Drugs to the rest of the body by blood
- 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
Drugs in kidney
- clears hydrophilic
- doesn't clear hydrophobic
27
properties associated with ADME
A: absorption
D: distribution
M: metabolism
E: excretion
28
Lipinksis rule of 5
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
hydrogen bond donors vs acceptors in LIPINSKI
donors: h is amount of donors
OH
NH
acceptors: only with lone pair
- N, O
30
rationale for h bonds
h bond increase water solubility
difficult to cross membrane
31
rationale for molecular weight
- large molecules less soluble (larger cavity in solvents)
- do not pass through tightly packed membrane
32
rationale for logP
water solubility decreases as lipophilicity increases
33
measurements for lipophilicty
- 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
advantages + disadvantages of Log P AND Log D
SEE ANSWER
35
2 common measurement methods
- solutions (separate layers)
- HPLC (high performance liquid chromatography)
36
what determines water solubility
- pKa: equilibrium constant related to removal of H
- ionization increases water solubility
37
pH and pKa
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
define amphiprotic
- can acts as base or acid
- water
- amines are usually bases, can act as acids but not useful in drug industry
39
pH effects on water and lipid solubility
- solubility in water increases as pH increases, increases hydrophilicity
- solubility in octane decreases as pH increases, decreases lipophilicity
40
what are the 3 factors that influence drug permeability
- rate at which drug passes through lipid membrane
- solubility, Log P, molecular weight
41
2 most common assays for permeability
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
benchmark values of commercial drugs
- 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
Metabolic stability: resistance to chemical change
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
catalytic cycle of enzyme:
see diagram
45
Phase II
- adds polar groups
- makes it easier for kidney to dispose
- glucuronic acid, sulfonation, acetylation, glutathione
46
2 common measurements of metabolism
- liver microsomes
- half-life measured (T1/2)
- plasma stability (T1/2)
47
process of optimization
- 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
techniques of molecular modification
- addition/deletion
- substitution
- chain extension/contraction
- ring expansion/contraction
- ring variations
- simplification
- rigidification
49
describe substitution + use of isosteres
- replace FGS
- groups of similar steric + electronics
- similar bio activity
- similar shapes/size
50
describe classical isosteres
- 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
describe non classical isosceles (bioisosteres)
- atoms or groups with similar chemical properties
- differ in electronics + steric
- can enhance metabolic stability, reduce side effects, etc
SEE EXAMPLES: tetrazole
52
describe chain extension/contraction
- better alignment and better binding to binding site
- SEE DIAGRAM
53
describe ring expansion and contraction
- can use heteroatoms
- SEE DIAGRAM
54
describe structure simplification
- remove parts that do not affect potency
- remove stereocenters
- take into account spacing for proper alignment
- SEE DIAGRAM
55
stereocenters and racemates
- 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
describe pharmacophore
- groups that are important for activity, part that is responsible for activity
biopharm
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