Drug Design: Molecular Interaction Flashcards
What happens if the hydrogen bonding between a receptor and ligand is of type 1?
Removal of the hydrogen by conversion to a methyl ether or an ester will block this bonding.
OH can be reacted with sodium hydride and a grignard to produce an ether,
OH can be reacted with an acid chloride to produce an ester
Thus in the absence of a H, no H bonding can take place
What is the role of hydroxyl groups in receptor ligand interaction?
They are usually involved in hydrogen bonding on the receptor
This can occur either via the hydrogen atom by interaction with a carbonyl group (or other lone pair donor) on the receptor
Or via the oxygen atom by interaction with an electron deficient hydrogen atom on the receptor
How can a OH group be completely removed?
By conversion to a mesylate or tosylate (reacting with sulphonyl chloride) followed by reduction with LiAlH4 leaving just the H
What is the problem with removing the hydroxyl group ?
Other functionality may not be comparable with the use of such strong reducing agents
What is the role of amino groups in ligand receptor binding?
Amines are involved in H bonding and ionic bonding to groups on the receptor.
Free amines can form salts that form ionic bonds with acidic groups in the receptor
What happens if an amine is converted to an amide?
This will prevent the involvement of lone pairs in hydrogen bonding
This will also prevent onion formation
What type of amine is dealkylated first?
Tertiary amines, this is done using cyanogen bromide in the Von Braun reaction
What is the role of aromatic rings in receptor ligand binding?
Aromatic rings are usually involved in VDW interactions with hydrophobic parts of a target site.
Remember that VDW forces = weak intermolecular forces operating over small distances. Attractive forces arise from the uneven distribution of use front over time.
When are VDW forces strongest between moieties?
When they can approach each other very closely.
Aromatic ic rings can interact with flat hydrophobic parts of a receptor resulting in π-π stacking
How can VDW via aromatic rings be weakened?
The aromatic ring can be hydrogenated to a cyclohexane making the structure no longer flat.
This weakens VDW interactions with the receptor
What is the role of double bonds in receptor ligand binding?
Double bonds can also undergo VDW interactions with hydrophobic regions of a receptor.
What can weaken the interaction between a double bond and a receptor?
Reduction to an alkane as it cannot approach the receptor surface as closely
What is the role of ketones in receptor ligand binding?
Ketones are a common functional group which can interact with a target via hydrogen bonding or dipole dipole interactions.
The ketone aligns to interact with a dipole moment in the target.
How can ketone binding be weakened?
Reduction to an alcohol weakens both types of interactions as the geometry and alignment of the functional group has now changed
What is the role of amides in receptor ligand binding?
Amides often interact with targets through hydrogen bonding of the carbonyl oxygen.
How can an amide interaction be weakened?
Amides can be removed by hydrolysis but this will split the molecule.
Amides can also be reduced to disrupt the hydrogen bonding involving the carbonyl oxygen.
What is an isostere?
A classical isostere is an atom or group of atoms having identical numbers of outer shell electrons.
A non classical isostere are those that differ by one parameter e.g. Size or electronegativity.
Why are isosteres useful in drug design?
Replacing potential binding groups with a classical isostere is a useful way of determining whether the binding group is important or not
What are some examples of isosteres?
SH, NH2, CH3 are isosteres of OH
S, NH, CH2 are isosteres of O
Hence replacing OH with CH3 can be used to determine if H bonding is taking place
And replacing OH with NH2 can be used to determine if H bonding remains
What is an example of a drug developed through the use of isosteres?
Propranolol which is a beta blocker, it has an ether linkage.
It was found that replacement of the ether with NHCH2 stains activity whereas replacement with CH2CH2 eliminated the activity.
This suggested the ether is a required binding group and probably binds via H bonding to the receptor
How was prontosil discovered?
By Gerhard Domag, a chemist/pathologist.
Found via serendipity that staphylococci and haemolytic streptococci was killed by an industrial dye called prontosil rubrum
After his daughter got infection from a needle, Domag adminstered a large dose of prontosil and she fully recovered.
Prontosil was synthesised and described in 1908
