Med Chem Exam 1

Front 1

Why are mechanism-based inhibitors more suitable for use as therapeutics

Back 1

Produce electrophile only after reaction with target enzyme

Front 2

alternative substrate

Back 2

doesn't inhibit the enzyme, but does inhibit the pathway

Front 3

Ways bacteria can become resistant

Back 3

- pump it out
-mutate binding site to make it more selective for PABA
-Modify the drug
-acetylate it, which would prevent it from reacting
-Increase PABA so it out competes Sulfanilamide

Front 4

multisubstrate analog inhibitors

Back 4

bring 2 substrates together to make a product

-Example is seen in Gentamacin : take 2 substrates that normally wouldn't bind together and tether them so when one binds, the other one just locks right in and so on
-Entropic: seems as if the concentration is high , but really is not. Binding is just occuring due to tethering

Front 5

IC50

Back 5

The lower the number the better

Front 6

Therapeutic example of multisubstrate analogs

Back 6

Parkinson's Disease: Inhibitors of COMT increase catechol neurotransmitter signaling to prevent breakdown of dopamine so that it stays in the system longer and treats one of the symptoms of the disease

Front 7

Transition State analogs

Back 7

Mimic the intermediate of the of the reaction. Chances are if the intermediate is mimicked, then the transition is also being mimicked because they are so similiar

Front 8

What kind of bonding to enzymes use

Back 8

H-bonding and vander waals interactions to lower energy

Front 9

Binding in Transition state analogs

Back 9

- occurs in tetrahedral state intermediate
- Carbon/nitrogen considered unstable for central atom
-enzyme binds to sp3 atom to stabilize tetrahedral shape

Front 10

reversible inhibitors

Back 10

-link together molecules to get more binding energy and an entropic advantage through kelation or to mimic a high energy intermediate to take advantage of amino acid. Flaw…almost always end up with polar molecules

Front 11

affinity labels

Back 11

combine substrate mimicry with a reactive electrophile
-since bonding is covalent, cannot detach substrate from enzyme
-Consists of Substrate with Nucleophile and Enzyme with Electrophile(reactive species)
-leads to irreversible inhibition of enzyme

Front 12

Kd=

Back 12

1/Ka

Front 13

Enthalpy( delta H)

Back 13

heat released or absorbed during a reaction

Front 14

S(delta S)=

Back 14

Rln(s) * where s is the number of possible micro states

Front 15

constitutive activity

Back 15

some level of activity in receptors when not bound to a ligand

-Inverse agonist will bind and reduce the activity of that receptor

Front 16

What is the effect when [Drug] >>>>Kd

Back 16

maximal effect

Front 17

What is the effect when [Drug] = Kd

Back 17

Effect is 1/2 maximal

Front 18

Ligand-gated ion channel

Back 18

Ex. Nicotinic /AcH receptors. Receptor binds to channel to cause activation of channel, which then allows ions to flow through.
-pentameric
-in synaptic cleft

Front 19

G-protein coupled receptor (metabotropic)

Back 19

-ligand binding leads to G-protein mediated production of second messengers

Front 20

Common example of G-protein

Back 20

serotonin binds to g-protein and causes a conformational change

Front 21

Steps to downstream effects in G-protein activation:

Back 21

1. Binding of agonist
2. Exchange of GDP for GTP
3. B, Y, sub units dissociate
4. alpha and GTP bind/activate Effector cell
5. GTP hydrolysis returns everything back to normal

Front 22

G- stimulatory

Back 22

Activates Ca+2 channels, activates adenylyl cyclase

Front 23

G-inhibitory

Back 23

activates K+ channels, inhibits adenylyl cyclase

Front 24

G0

Back 24

inhibits Ca++ channels

Front 25

Gq

Back 25

activates phospholipase C

Front 26

G 12/13

Back 26

Diverse ion transporter interactions

Front 27

Bioisosterism

Back 27

lead optimization by atom or group replacement
- same # valence electrons, but may different in # of atoms
-or similarity in biological activity

Front 28

Importance of chirality in enanitomers

Back 28

allows the molecules to fit in protein pockets correctly. If the structure is changed or the atoms are rotated differently than that could change the effect of binding

Front 29

enantiomers

Back 29

sterochemistry is opposite of each other

Front 30

diastereomer

Back 30

more than 1 chiral center but not mirror images of each other

Front 31

4 major strategies for producing stereochemically pure compounds

Back 31

1. Make use of natures chiral pool
2. separate racemic mixture by converting into diastereomic salts
3. use an enzyme to create chiral center or resolve enantiomeric mixture
4. use a synthetic chiral catalyst

Front 32

Why are drugs with chiral centers being marketed as pure enantiomers?

Back 32

1. potentially safer than racemates
2. economic incentive to extend patent life of racemates
3. New Drug Entities being marketed are now either achiral or pure enantiomers

Front 33

What is key to conformational restriction?

Back 33

1 or more cyclic structures

Front 34

Ways to optimize lead compounds to drugs

Back 34

1. Absorption- transport from GI tract into circulation
2. Distribution- penetration of tissue or for CNS passage across BBB
3. Metabolism- predictable metabolic breakdown to enable stable dosing
4. excretion- predictable excretion pattern
5. toxicity- limited human toxicity, wide therapeutic index ( Large LD 50/ ED 50 )

Front 35

Difference between active and passive transport

Back 35

active transport requires specificity and saturation can happen. passive yields a straight diagnol line because saturation does not occur, drug is lipophillic enough to pass through

Front 36

What Pka is most favored for drugs to cross the BBB?

Back 36

Neutral PH or as close to neutral as possible

Front 37

how does lipophilicity affect absorption

Back 37

the greasier( more lipophilic ) a compound is, the more likely it is to pass through the membrane

Front 38

To calculate logP using pie values

Back 38

count up the amount of different functional groups. multiply the pie value for each functional group by the amount of groups.. Sum everything up and that is your logP value

Front 39

what is logP a measure of

Back 39

lipophobicity

Front 40

Molecules with a log P > 0.5

Back 40

are less soluble

Front 41

Lipinski's Rules:

Back 41

Drugs are less likely to be orally active drugs if they have the following properties:
1. there are more than 5 H-bond donors(exressed as the sum of -OH and -NH)
2. The molecular weight is more than 500
3. The log P is more than 5
There are more than 10 H-bond acceptors( expressed as the sum of Nitrogens and Oxygens)