422 Exam2 Alyah's notes

Order of reactivity based on height

Clavams > Carbapenems > Penams > Cephams > Monobactams

Huchel’s Rule for aromaticity

Must have 4n + 2 = pi electrons

N is zero or positive integer (1, 2, 3, etc.)

Best CNS drugs are

smaller, minimally flexible, minimally hydrophobic, and neutral or basic (NOT acidic)

The higher the fraction of sp3 carbons, the (more/less) soluble the drug is

more, higher logS because the more flat a molecule, the more stacking can occur → harder to interact with water molecules and for the molecule to dissolve

Imino groups in 7-membered heterocycles are

Conjugate acids have pKa between

basic

2-4

Too many flexible bonds gives

poor solubility b/c too great of a loss of entropy when the ligand binds to a receptor

Β-Lactams are antibiotics that target

cell wall synthesis

B-lactams, the higher the height of the ring

the more reactive

Low reactivity B-lactams are used to

inhibit B-lactamases

3-membered rings have

distorted angles → very reactive

Nitrogen five membered heterocycle (can/can not) undergo resonance

can

Sulfur five membered heterocycle (can/can not) undergo resonance

can not because it does not share electrons

Nitrogen containing aromatic heterocycles are

weak bases with strong conjugate acids 

Sulfur containing aromatic heterocycles are

neither acidic or basic. They are more hydrophobic than nitrogen containing heterocycles 

5-membered aromatic heterocycles are 

flat

6-membered aromatic heterocycles are

flat

tetrahedral shape that is not flat

sp3

trigonal planar that is flat

sp2

The less flat the molecule is

the more reactive it is

More aromatic rings =

more flat

CNS drugs overall are more

lipophilic than non-CNS drugs 

A molecule with lots of hydrogen bonding/donating, heavier molecular wt., higher PSA, it is probably a

non-CNS drug

6-membered nitrogen tend to be (more/less) reactive than 5-membered nitrogen containing heterocycles

less reactive

7-membered rings

are not planar

Unsaturated 7-membered heterocycles are

anti-aromatic

No drugs have 7-membered sulfur containing saturated heterocycles because

they can’t be metabolized

Electrostatic interactions can occur at a

further distance

Short range repulsions can only occur at a

very small distance 

Partition Coefficient: LogP 

Higher logP

P = [drug]octanol / [drug]water 

Drug needs to be unionized

the drug is more lipophilic 

Distribution Coefficient: LogD 

Higher the pH, the (higher/lower) logD 

Higher pH, the drug becomes (ionized/unionized)

P = [drug]ionized octanol + [drug]unionized octanol   /   [drug]ionized aq + [drug]unionized aq 

Drug can be ionized

lower → more hydrophilic

ionized → moves out of the octanol phase into the aqueous phase 

The higher the TPSA, the (more/less) polar the molecule is

>140 angstrom

>90

more polar and less likely it will cross cell membranes 

poor cell membrane permeability 

poor blood brain barrier permeability 

TPSA

topological polar surface area. Surface area of all the polar parts of a molecule

HSA

hydrophobic surface area. Surface area of all the hydrophobic parts of a molecule

Density of packing

takes more energy to disrupt aromatic ring stacking and allow them to interact with water molecules to dissolve

Uptake transporters

help absorption of drugs in intestines, in hepatocytes for biliary/metabolic clearance, and help distribution into organs

Efflux Transporters

prevent toxic compounds from building up, efflux them back out. Stop distribution on drugs into certain organs like brain

Substrates for Oligopeptide transporters (PEPT1, PEPT2)

dipeptides and tripeptides. If a drug has poor absorption, can add an amino acid appendage so it will be a substrate for PEPT1/2 and be absorbed better

Large neutral amino acid transporter (LAT1)

transports amino acids and certain drugs (L-Dopa) across the apical membrane on the epithelial cells of the blood brain barrier (BBB)

Monocarboxylic acid transporter (MCT1)

on the epithelial cells of the BBB and the intestines transports salicylic acid and certain statin drugs

Organic anion transporter polypeptide (OATP1)

transports antibiotics, NSAIDs, antivirals, AZT, acyclovir, etc into the renal tubule cells for drug excretion

Enthalpy

(H) total heat energy in a system = internal energy of system + (pressure)*(volume)

Entropy

(S) unavailability of a system’s thermal energy to do mechanical work = disorder

If Gibb’s free energy is negative

the reaction is thermodynamically favorable 

Receptor-ligand binding process

Kon (___) vs. Koff (___) 

Kd =  

the lower the Kd, 

Water molecules must be removed from receptor site before the drug can bind. Once the drug binds, water molecules can re-solvate the ligand with the receptor but there will be less water molecules this time

Kon: association constant

Koff: dissociation constant 

Kd = Koff/Kon → lower Kd, the more likely the ligand won’t stay bound to the receptor

Enzyme Inhibition Non-covalent

when the ligand binds to the enzyme, no chemical bond is made

Enzyme Inhibition Covalent

when the ligand binds to the enzyme, a covalent chemical bond is made. Can be reversible or irreversible. Many antibiotics act irreversibly 

The Hydrophobic Effect

when water molecules (high energy state of random hydrogen bonding) surround a hydrophobic molecule by forming structures spheres around the molecule 

Hydrophobic molecule is introduced

entropy decreases, so when the molecule “hides” in a hydrophobic pocket, this decrease in entropy is minimized 

Cooperativity

all interactions between molecules working together

Positive cooperativity

binding energy associated with multiple interactions working together is larger than the sum of their individual binding free energies

Don’t want to decrease entropy because

that would increase ∆G which is thermodynamically NOT favored

Main driving force for ligand-receptor binding

If a ligand comes in and removes the structured water from the hydrophobic pocket, the water can randomly hydrogen bind again, entropy increases, and the reaction is thermodynamically favored 

Kon

The higher Kon

association constant (s-1 ), amount of time ligand is associated with receptor 

the more likely that the ligand will be bound to the receptor 

Koff

The lower Koff

dissociation constant (s-1 ), amount of time ligand is dissociated from receptor

the more likely that the ligand will be bound to the receptor

KD

Lower Kd

dissociation constant (more accurate) = Koff/Kon = [R][L]/[RL] (unit = M). Inversely represents the amount of ligand that is bound to receptor 

ligand is more strongly bound to the receptor (higher affinity between ligand and receptor) 

Ki

Lower Ki

inhibition constant. Almost equivalent to KD. Represents the concentration required to produce half maximum inhibition 

less ligand is required to cause inhibition of the enzyme (it’s easier for the ligand to bind to the receptor) 

∆G = -RT*ln(Ki) The lower Ki the

Lower the ∆G

higher the ∆G → less likely the ligand will dissociate from the receptor 

the more favorable the reaction is

1-2 hydrogen bonds gives

1 order in Ki (Going from Ki = 100 nM to Ki 10 nM) 

Addition of a methyl group in the n=binding pocket gives

a 10-fold increase in potency (Going from Ki = 1 nM to Ki = 100 pM)

Takes ____ of energy to release structural water

1-2 kcal/mol

Purpose of receptors, ion channels, and transporters

accelerate the permeation of molecules across membranes

Purpose of 3- and 4- membered heterocycles

have the right shape and electronic distribution to be recognized as a ligand by a receptor

Purpose of B-lactam resembling D-alanine D-alanine terminal of peptidoglycan strand

so it can act as a ligand for DD transpeptidase and doesn’t allow it to finish synthesizing the peptidoglycan strand

Purpose of B-lactam acting as a ligand for DD transpeptidase

to make a covalent bond → reaction is irreversible

Purpose of privileged scaffolds

common building blocks used in making drugs that interact with common protein motifs (alpha-helix, beta-turn, gamma-turn, beta-strand)