lect 3

Question 1

How do Drugs binds to target using non-bonding interactions

Answer 1

• Molecule recognition by matching a pattern of noncovalent interactions
  o If it doesn’t match drug will leave
• Some drugs bind covalently
  o Recognize target by noncovalent binding groups
   Covalent interactions succeed due to noncovalent binding

Question 2

electrostatic interactions

Answer 2

o Strongest
o Strength depends on outside environment (stringer in hydrophobic environments)
o Non directional +/- can be anywhere
o Drug needs to be surrounded by hydrophobic environment
 b/c polar molecules can get in b/w ions and separate them and the crystal dissolves
 nonpolar molecules aren’t strong enough to break electrostatic interactions

Question 3

hydrogen bonding

Answer 3

o 2nd strongest
o H in O-X bond attracted to non bonded electrons on nearby atoms
o Stronger in hydrophobic environ
o Directional; should be on the same angle
o H bond donors—provide the hydrogen (OH,NH)
o H bond acceptors (provide lone pair to form H bond) (N, O/ bad is S)

Question 4

dipole-dipole

Answer 4

o Moderate strength
o Stronger in hydrophobic interactions
o Carbonyls strong e w/drawing groups (C=O)

Question 5

van der waals

Answer 5

o Weakest
o Strength depends on surface area (larger SA, stronger)
o Lipophilicity
o De-solvation
 Empty binding pockets (lipophilic) are full of H2O
 H2O molecules are stripped away as drug enters binding site (polar drugs cling to H2O

Question 6

optimizing a drug

Answer 6

• Lipophilic
• Potency—concentration of drug required to achieve effect
  o Low con= high potency (tightness of sticking)
• SAR (structure activity relationships)
  o Structural changes to drug
  o Measure potency
  o Relate effects to structural change
• SPR (Structural property relationships)
  o Structural changes to a molecule
  o Measure various properties
  o Relate effects to structural change

Question 7

goal of drug

Answer 7

• Drug like
• Potent (small dose)
• Bioavailable-enter the body (%)
• Good chem behaviour (solid/liquid, stability, ease of synthesis)
• Properties (solubility, pka, logp/d, molecular weight, permeability, melting pt, metabolism, protein binding)

Question 8

GI Tract

Answer 8

• Not all drugs will pass the barrier, must optimize the amt that can
• Stomach pH 1.4-2.1
  o Must be water soluble
  o Must survive strong acid
  o No drug is absorbed in stomach

Question 9

intestinal environment

Answer 9

• Mildly acidic ph 4.4-6.8
• Bile salts—solublize lipophilic drugs (surfactant)
• Drugs must passively diffuse through intestine
  o Drug must be hydrophilic and phobic at the same time b/c of polar heads and nonpolar tails on phospholipid bilayer
   Must dissolve in H2O
   Must dissolve in tails
• Works by having it as an acid (neutral) to lose proton in phillic environ and in phobic environ it is - charged
• Or as a base charged +/- in phobic environ it is neutral
• Once it leaves intestine the drug is charged
  o Most drugs are basic (70%), acidic (20%), or neutral (5%)

Question 10

liver

Answer 10

• Detoxify food
• Metabolized to be removed from blood
  o Nonpolar (toxic)  polar (non toxic)
• Metabolism
  o Phase I: oxidation
  o Phase II: conjugation (attach to other groups to make it water soluble

Question 11

blood

Answer 11

• Drugs transported to body via blood
• Blood is water, polar drugs dissolve easily
• Lipophilic molecules bind to carrier proteins in blood (Not suggested)
• Has hydrolytic enzymes—destroy drug
  o Esterase—break ester bonds
  o Proteases (break amide bonds)

Question 12

kidney

Answer 12

• Clears substances from the blood
• Gets rid of polar things (drug cant be too polar)
• Lipophilic molecules not easily removed

Question 13

barriers for a drug to produce a response ADME

Answer 13

• Absorption
• Distribution
• Metabolism
• Excretion

Question 14

Lipiniski’s Rule 5

Answer 14

meet 2 of these rules then IT WILL NOT BE WELL ABSORBED
o More than 5 hydrogen bond donors (OH/NH)

 H bonds > water solubility
 Reduce lipophilicity
* Make it hard to cross lipophilic membrane
* Count all H’s

o More than 10 hydrogen acceptors (N’s and O’s)

o Molecular weight > 500

 Large molecules are less soluble and have small surface area, want the opposite

o LogP > 5
 MLogP >4.15
 Measurement of lipophilicity

Question 15

logp

Answer 15

o LogP= Log(drug in octanol)/drug in water)
o Drug is in NEUTRAL form
o AT ANY PH BUFFER—CON
 NOT MADE IN PHYSIOLOGICAL CONDITONS FOR THE BODY
o High #–lipophilic
o Low #hydrophlic
o FDA like its
o Correlates to rule of 5

Question 16

logd

Answer 16

o =log(drug in octanol/drug in water) at a given pH of 7.4
 pH of blood
 1<LogD 7.4< 3
o Easier to measure b/c fixed pH
o Correlates well with rule of 5
o Physiological relevance
o Less used

Question 17

molecules protonated when

Answer 17

pH < pKa
o Acids
 Neutral pH < pKa
 Charged pH > pKa
o Bases
 Neutral pH > pKa
 Charged pH < pKa

Question 18

protonation

Answer 18

• Consider pH range -1.7—15.7 (in water)
  o pKa < -1.7 deprotonated
  o pKa > 15.7 protonated
• best pKa is 2-3 units away from 7.4

Question 19

steps for determining pKa

Answer 19

o draw the acid-base reaction (acid on left and base on right)
 if you don’t know if its an acid/base, draw both. With the given image and with the protonated/deprotonated image
o find the pKa of the acids
o check the range is it within -1.7—15.7?

Question 20

steps for ionization

Answer 20

o do the same for pKa if you don’t know, to use the right pKa
o use the pKa to see if it is charged/neutral and protonated/deprotonated
 pka > 7.4 UNPROTONATED
 pka > 7.4 NEUTRAL & INSOLUBLE

Question 21

steps for molecules with multiple groups

Answer 21

o Find the pKa for all the groups
o Make a line across page—one end is low ph the other is high pH
o Draw the normal molecule first then put reverse arrows and underneath them put < lowest pKa in the molecule
o Then draw the molecule with the lowest pKa deprotonated
o Then draw reverse arrows with next biggest pKa and draw the next group deprotonated
 For each molecule see if soluble
* If it is charged it is SOLUBLE

Question 22

drug permeability

Answer 22

• Influenced by solubility, LogP, molecular weight

Question 23

drug permeability caco-2

Answer 23

 Human colon carcinoma cells similar to human intestine
 Test if drug passes that
 Hard to do
Test to see at what rate it is transported to buffer 2

Question 24

drug permeability PAMPA

Answer 24

 artificial membrane
 lipid
 Easily done
 Not realistic
o Test to see at what rate it is transported to buffer 2

Question 25

metabolic stability

Answer 25

• Phase 1
  o Add polar groups to reduce lipophilicity
   Oxidation (sigma to pi bonds) or hydrolysis
• Phase 2
   Conjugation (add groups) to improve water solubility

Question 26

SPR

Answer 26

• Effect of structure on molecular properties
  o Potency
  o Solubility
  o Melting point
  o pKa
   make molecule and see if these qualities in it are beneficial or not

Question 27

Drug optimization

Answer 27

• lead structure
• make related compounds and test 1 factor at a time
• measure potency
• use patterns to identify site on molecule that needs to be changed/not and modifications that are good or bad