Chirality in drug design Flashcards
What are enantiomers?
A pair of stereoisomers that are non-identical mirror images of each other.
What are diastereoisomers?
A pair of non-identical stereoisomers that are not mirror images of each other - arise in molecules with 2 or more chiral centres
What is a stereoisomer?
2 or more compounds differing only in the spacial arrangement of their atoms
what is a Meso compound?
A non-optically active stereoisomer
What is optical activity?
the ability to rotate a plane of polarized light. d =rotates a plane clockwise l=anti-clockwise
Does a racemic mixture have optical activity?
No, both enantiomers will rotate light in opposite directions so will cancel each other out.
How can our noses distinguish between the smell of the enantiomers of carvone?
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
What two approaches do we use to obtain a pure chiral molecule?
- ) Chiral separation
2. ) Chiral pool
What is chiral separation?
Use a physical method e.g. chromatography (HPLC) to separate and obtain the desired stereoisomer from the mixture
What is the chiral pool?
Where we use a product from nature that already has a chiral centre as the starting material
When is the chiral pool useful?
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..
What is a raceimic mixture / racemate?
Contains an equal amount of both stereoisomers. Warfarin is given as a racemate
For a pair of stereoisomers, which is the EUTOMER and which Is the DISTOMER?
Eutome = the isomer with the greatest activity Distomer = isomer with the lower activity
What is the ratio between the eutomer and distomer called?
The eudismic ratio
what can be the problem with administering a drug as a racemate?
One of the enantiomers might have significant less activity than the other = a large portion of the dose is inactive.
Pairs of enantiomers mostly cross cell membranes by passive diffusion. Would their different chirality affect passive diffusion?
No, both would cross the membrane via passive diffusion with equal ease
would the different chirality of the enantiomers affect the way they diffuse via active transport?
Yes, they are transported by trans-membrane proteins which are chiral and so their different stereoisomers will be transported differently = THIS AFFECTS ABSORPTION.
How does stereochemistry affect distribution?
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)
How does stereochemistry affect metabolism?
Metabolism is controlled by enzymes which are chiral so will recognise the different enantiomers and metabolise them differently.
What is the chiral switch?
The development of a single isomer drug that was previously marketed as a racemate.
When is it acceptable to give a drug as a racemate?
When neither of the enantiomers cause harm. It is cheaper not to separate them.
What are the advantages of the chiral switch?
- ) Improved biological activity as all the drug is active
- ) More selective = no off target binding = less SE’s
- )Modified dosage (lower dose needed as all is active) e.g. single dextroratory isomer of ibuprofen is effective at half the dose.
- ) Simpler pharmacokinetics and pharmacodynamics
- ) An opportunity to market a new drug
