Drug structures and bonds Flashcards
To get a strong interaction between a drug and it’s target what does a drug need to be?
- The drug needs to be the right size and shape to fit into the binding domain
- The drug needs the right atoms to be in the right place, if it is going to make bonds with the protein target
What is the phamacophore?
The arrangement of chemical groups within a molecule that is necessary for biological activity
What are optical isomers?
compounds in which there is a different 3D arrangement of functional groups about one or more atoms. These atoms are called chiral centres
What are the two types of optical isomers?
enantiomers which are pairs of molecules that are non-superimposable mirror images of each other and diastereoisomers, which are molecules that are not mirror images but which differ in the orientation of one or more chiral centres
How do enantiomers differ between each other?
differ in that solutions of the compounds will rotate polarised light in opposite directions. They also differ in how they interact with biological systems
What type of isomerism is optical isomerism?
A type of stereoisomerism
Why is optical isomerism important in drug binding?
- When a drug is optically active, one enantiomer will bind tighter to it’s protein target than the other.
- When we try to fit the ‘wrong; optical isomer of a drug into the protein binding site there isn’t as good a match between the bonding residues in the drug and the binding site, we won’t see as strong a binding reaction
What is the general principle about the binding of optical isomers?
If a protein selects between optical isomers of a drug, the drug must make at least three points of attachment to the protein
How do you classify enantiomeric pairs by optical activity?
- Enantiomers rotate polarised light in opposite directions
- Enantiomers that rotate light in a clockwise direction are called d- or (+) e.g. d-nicotine (+) glutamate
- Enantiomers that rotate light in an anticlockwise direction are called l- or (-) e.g. l-nicotine
- The d and l must be written in lower case
- The rotation of polarised light can be measured using a polarimeter
How do you classify enantiomeric pairs by configuration (the D/L system)?
- This system is only used for monosaccharides and amino acids e.g. D-glucose; L-aspartate
- In the D/L system, molecules whose structure can be ‘related back’ to the (+) enantiomer of glyceraldehyde are classified as D and those that can be related back to the (-) enantiomer of glyceraldehyde are called L.
- All naturally occurring amino acids (except glycine) are in the L configuration
- This system provides structural information, but it is only applicable to a limited range of compounds
- The D/L system does not have a one: one correlation with the +/- system or the R/S system
How do you classify enantiomer pairs by configuration? (the Cahn-Ingold Prelog (R/S) system?
• It allows you to work out the structure of the molecule from its designation:
- Identify the chiral centre. Usually it will be a carbon with four different substituents
- Prioritise the substituents according to the atomic number of the atom connected to the chiral centre
- If two substituent atoms have the same atomic number, work your way out concurrently along the two chains until a point of difference is found. The priorities are then assigned at that point of difference. At the point of difference, priority is assigned on the basis of the highest atomic number. For example -CH2-Cl has higher priority than CH2-CH2-CCl3 because at the first point of difference, Cl has a higher atomic number than C
- If a double bond is present, treat it as two single bonds to the same type of atom
- Once priorities have been assigned, orient the molecule so that the lowest priority group faces away from you
- If the other groups are arranged in clockwise descending order of priority, the chiral centre is in the R configuration
- If the other groups are arranged in an anticlockwise descending order of priority, the chiral centre is in the S configuration.
How does noradrenaline work in stereoselective drug interactions?
The R version of noradrenaline binds to B2 adrenoceptors around 45x tighter than the S version
How does Citalopram work in stereoselective drug interactions?
- Citalopram is an antidepressant in the same SSRI family as fluoxetine (Prozac). It was originally marketed as racemic mixture (50:50 from R and S). However, it was soon discovered that only the S form of the drug had antidepressant properties – it binds to the target protein (the serotonin transporter SERT) about 50x tighter than the R form.
- The manufacturer was able to re-patent citalopram as the pure S isomer which was marketed under the name escitalopram. It has been found that escitalopram is modestly more effective than the racemic mixture and has a slightly lower risk of side effects.
What are the rules about identifying the chiral centre with the Cahn-Ingold-Prelog system?
- In most cases the chiral centre will be a carbon with four different groups attached
- Some molecules may have more than one chiral centre. Each of these centres is classified separately as R or S.
- Molecules with no chiral centres are termed achiral
What are the rules about rotating the molecule with the Cahn-Ingold-Prelog system?
- The next stage is to mentally rotate the molecules so that the lowest priority group (H often) is facing away from you, into the screen
- Then look at the groups that face you. If they go from highest priority (1) to lowest in clockwise order, then the molecule is R
- If they go from highest to lowest in anticlockwise order, then the molecule is S
