Chirality in drug design

Question 1

What are enantiomers?

Answer 1

A pair of stereoisomers that are non-identical mirror images of each other.

Question 2

What are diastereoisomers?

Answer 2

A pair of non-identical stereoisomers that are not mirror images of each other - arise in molecules with 2 or more chiral centres

Question 3

What is a stereoisomer?

Answer 3

2 or more compounds differing only in the spacial arrangement of their atoms

Question 4

what is a Meso compound?

Answer 4

A non-optically active stereoisomer

Question 5

What is optical activity?

Answer 5

the ability to rotate a plane of polarized light. d =rotates a plane clockwise l=anti-clockwise

Question 6

Does a racemic mixture have optical activity?

Answer 6

No, both enantiomers will rotate light in opposite directions so will cancel each other out.

Question 7

How can our noses distinguish between the smell of the enantiomers of carvone?

Answer 7

Our sense of smell is governed by olfactory receptors = a protein which is chiral. Since receptors have chiral preference for their substrates it is likely that the enantiomers bind to different receptors

Question 8

What two approaches do we use to obtain a pure chiral molecule?

Answer 8

1. ) Chiral separation

2. ) Chiral pool

Question 9

What is chiral separation?

Answer 9

Use a physical method e.g. chromatography (HPLC) to separate and obtain the desired stereoisomer from the mixture

Question 10

What is the chiral pool?

Answer 10

Where we use a product from nature that already has a chiral centre as the starting material

Question 11

When is the chiral pool useful?

Answer 11

When trying to synthesise a molecule with several chiral centres = very difficult e.g. tamiflu has 3 chiral centres so we use a product from nature (shikimic acid) which has 3 chiral centres in the same place but in different orientations. We can manipulate it to produce tamiflu..

Question 12

What is a raceimic mixture / racemate?

Answer 12

Contains an equal amount of both stereoisomers. Warfarin is given as a racemate

Question 13

For a pair of stereoisomers, which is the EUTOMER and which Is the DISTOMER?

Answer 13

Eutome = the isomer with the greatest activity
Distomer = isomer with the lower activity

Question 14

What is the ratio between the eutomer and distomer called?

Answer 14

The eudismic ratio

Question 15

what can be the problem with administering a drug as a racemate?

Answer 15

One of the enantiomers might have significant less activity than the other = a large portion of the dose is inactive.

Question 16

Pairs of enantiomers mostly cross cell membranes by passive diffusion. Would their different chirality affect passive diffusion?

Answer 16

No, both would cross the membrane via passive diffusion with equal ease

Question 17

would the different chirality of the enantiomers affect the way they diffuse via active transport?

Answer 17

Yes, they are transported by trans-membrane proteins which are chiral and so their different stereoisomers will be transported differently = THIS AFFECTS ABSORPTION.

Question 18

How does stereochemistry affect distribution?

Answer 18

Most drugs are transported in the blood by reversibly binding to plasma proteins e.g. albumin. Different stereoisomers will bind with different affinities (small effect)

Question 19

How does stereochemistry affect metabolism?

Answer 19

Metabolism is controlled by enzymes which are chiral so will recognise the different enantiomers and metabolise them differently.

Question 20

What is the chiral switch?

Answer 20

The development of a single isomer drug that was previously marketed as a racemate.

Question 21

When is it acceptable to give a drug as a racemate?

Answer 21

When neither of the enantiomers cause harm. It is cheaper not to separate them.

Question 22

What are the advantages of the chiral switch?

Answer 22

1. ) Improved biological activity as all the drug is active
2. ) More selective = no off target binding = less SE’s
3. )Modified dosage (lower dose needed as all is active) e.g. single dextroratory isomer of ibuprofen is effective at half the dose.
4. ) Simpler pharmacokinetics and pharmacodynamics
5. ) An opportunity to market a new drug