lect 3 Flashcards
How do Drugs binds to target using non-bonding interactions
- 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
electrostatic interactions
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
hydrogen bonding
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)
dipole-dipole
o Moderate strength
o Stronger in hydrophobic interactions
o Carbonyls strong e w/drawing groups (C=O)
van der waals
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
optimizing a drug
- 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
goal of drug
- 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)
GI Tract
- 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
intestinal environment
- 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%)
liver
- 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
blood
- 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)
kidney
- Clears substances from the blood
- Gets rid of polar things (drug cant be too polar)
- Lipophilic molecules not easily removed
barriers for a drug to produce a response ADME
- Absorption
- Distribution
- Metabolism
- Excretion
Lipiniski’s Rule 5
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
logp
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
logd
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
molecules protonated when
pH < pKa
o Acids
Neutral pH < pKa
Charged pH > pKa
o Bases
Neutral pH > pKa
Charged pH < pKa
protonation
- 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
steps for determining pKa
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?
steps for ionization
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
steps for molecules with multiple groups
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
drug permeability
- Influenced by solubility, LogP, molecular weight
drug permeability caco-2
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
drug permeability PAMPA
artificial membrane
lipid
Easily done
Not realistic
o Test to see at what rate it is transported to buffer 2
metabolic stability
- 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
SPR
- 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
Drug optimization
- 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
