Lec 5 Drug Shape

Front 1

What is bioisosterism? Why do we do it?

Back 1

Changing out functional groups.

When a drug lead shows toxicity or we wish to improve on a drug,
- can improve pharmacokinetic properties (ie t½)

Front 2

What is classical classification?

Back 2

any group that have the same number of valence electrons, though they may differ in number of atoms

- more structure than function, so not very relevant to us

Front 3

What is non-classical classification?

Back 3

do not have same number of atoms and do not fit steric and electronic rules of classical classification, but DO produce a similarity in biological activity

- eg they are functionally equivalent

Front 4

What is the reasoning behind marketing chiral atoms as pure enantiomers?

Back 4

1. potentially safer than racemates
2. economic incentive to extend patent life of racemates

Front 5

Isosteres

Back 5

native functional groups of interest

Front 6

Enantiomers

Back 6

mirror images

Front 7

Diastereomers

Back 7

molecules with two or more chiral centers and are NOT mirror images

Front 8

What is the relationship between the number of sterioisomers a drug has and the risk of side effects?

Back 8

The higher the number of stereoisomers, the more likely you are to have side effects

Front 9

What is the difference between Z and E isomers?

Back 9

Z isomers are cis to the double bond

E isomers are trans to the double bond

They are geometric isomers

Front 10

Thalidomide

Back 10

The morning sickness drug that caused birth defects
- acidic proton on a chiral center is easily deprotonated in vivo which tautomerizes back to the racemere

Has renewed interest as an anti-cancer drug due to its anti-angiogenic properties (angiogenesis is critical step in metastatis)

Front 11

How can fluorine make a molecule more stable?

Back 11

By replacing an easily deprotonated proton with F. No base can pull off the F

Front 12

Which is the more active enantiomer of Omeprazole?

Why?

Back 12

S is more active (Esomeprazole/Nexium)
- R is metabolized by a CYP450 that show a high degree of polymorphism

Front 13

What are the strategies for preparation of pure enantiomers of chiral compounds?

Back 13

1. Make use of nature's "chiral pool" (add final touches to a natural sugar, aa,etc.)
2. Separate racemic mixture by converting into diasteromeric salts that can be separtated (inexpensive, but needs acid or base functional group)
3. Use an enzyme to create chiral center or resove enantiomeric mixture
Adv: enzymes are specific
Dis: enzymes are specific
4. Use a synthetic chiral catalyst (stereochemical induction)
- increasing number of chiral reagents available

Front 14

How can gauche be the preferred conformation?

Back 14

functional groups may share electron density that makes the conformation more favorable

Front 15

Bioactive conformation∆

Back 15

only one conformation of a ligand will be bioactive,
hopefully the energy of binding is greater than the energy of the conformation conversion

∆Gbind = ∆Ginter - ∆Gconf (needs to be favorable)

Usually, ∆Ginter is negative while ∆Gconf is positive

Front 16

Conformational restriction

Class Example?

Back 16

a means of pre-organizing drug structure to be more like target bound species than a free species

- eliminates need of drug to overcome ∆Gconf

Examples:
- Cholrismate Mutase
- Penicillins

Front 17

isosterism

Back 17

mimicking of specific functionalgroups that make key interactions with a given target