ANS 8- Drug design - simple substitutions

How does structure affect function?

• there is a link between the chemical group - and function - can result in different responses

What is a structure activity relationships ?

-It describes the interaction /relationship between the structure and its function

-what functional groups are actually needed or part of the functions are relevant

What do the interactions at the receptor depend on ?

1. Types of functional groups

2. number of functional groups

3. relative arrangement of functional groups

How do we design a new drug?

• design a new drug from a natural ligand- new lead compound

5 steps :

• identify the types of interactions possible- How could it bind

• identify the important structural features (simplification)- remove some interactions, see if it works

• develop a structure-activity relationship- written

• identify a pharmacophore- a diagram ( the similarities)

• modify its pharmaceutical properties - is it soluble, suitable for a patient, etc

What are the drug properties for the lead/natural ligand?

• Usually, the lead is not selective between different receptor subtypes with different biological activities

• Usually not good ‘drug-like’ properties leading to difficult delivery

• need to make it selective to receptor types

How do you determine the interactions ?

• look at what can be protonated or deprotonated - results in charges +,- = ionic bond interactions

• look at hba,hbd = hydrogen bond

• aromatic - pi-pi stacking

• van der Waals interactions- from any alkyl chains throughout molecules

What are the 3 changes to enhance binding activity and drug-like characteristics?

1. simple substitutions- removing, changing groups

isosteres,biosteres

2. Altering 3d shape - stereochemistry,rigidification

3. Chain extension - exploit additional interactions - making it more complex- better binding

NOTE- You can only change one at a time

Describe the simple substitutions-Ionic interactions

At physiological pH, it is generally only from

Quaternary ammoniums

Protonated amines

Deprotonated carboxylic acids

What substitution would you do for a Quaternary ammoniums?

• Replace with a carbon

• Same shape – tetrahedral

• No charge

No activity - the ionic was essential

active- not needed

What substitution would you do for a tertiary amine?

Replace with an amide

Nitrogen in an amide is not able to become charged

no longer shows activity- amine is essential to activity

The molecule is still active -the amine is not interacting through an ionic interaction

What substitution would you do for a carboxylic acid?

Replace with

• an aldehyde- cannot be deprotonated at physiological ph

• an aliphatic alcohol- not deprotonated at physiological pH

• an ester- worst option, methyl larger than h

Describe the simple substitution - hydrogen bonding interactions

Groups that are BOTH Hydrogen Bond Donors and Acceptors

Groups that are acceptors

Groups that are donors

Note - usually make a series of changes due to Hba,hbd

What substitutions would you do for a phenol and alcohol?

Oxygen can be an acceptor

Hydrogen can be a donor

Can prepare an ether- gets rid of hbd , reduces hba activity - better change

an ester- gets rid of hbd,more likely to reduce h bond activity

What changes would you make for a ketone and an aldehyde ?

Oxygen in carbonyl can be an acceptor

Two possible interactions

Can reduce to alcohol- larger distance = weaker

Still keeps H-bonding potential, but changes the shape of the molecule

Carbonyl is planar and sp2

Alcohol is tetrahedral and sp3

Likely to weaken any H-bonding interaction

What substitutions would you make for an amide?

Oxygen in carbonyl can be an acceptor

Two possible interactions

Nitrogen in amide CANNOT act as a H-bond acceptor

Can act as an H-bond donor- remove donor methylated -rigid as an amine

remove acceptor - amine - not rigid - rotation too much of a change

alkene- donor and acceptor removes the rigidity

ketone - donor removed - not rigid

Note- for amides, you make a combination of changes

What substitutions do you do for a rings ?

• use another atom - for pyrrole goes from donor - acceptor - heteroatoms, e.g., furan, thiophene

• for pyridine acceptor - benzene neither - pyridinium ion ionic

What substitutions would you do for esters ?

Oxygen can act as an acceptor

Carbonyl more likely-more exposed,higher electron density

Could replace with an ether - removes carbonyl

What is the bigger issue when substituting for esters ?

Bigger issue:

• lack of stability

• easily enzymatically hydrolysed in the body

• easily chemically hydrolysed on storage

• may need to be replaced by a bioisostere

What is an isostere ?

Isostere: Atoms or groups that have the same valency and similar chemical and physical properties

eg - ether to a carbon chain

alcohol - to a carbon chain

What is a bioisostere ?

Bioisostere: A chemical group used to replace another chemical group within the drug without affecting the important biological activity whilst improving the pharmaceutical properties- keeps the binding interactions

What would you do for an ester?

Carbamate (urethane), the carbonyl is stabilised to nucleophilic attack by donation of electrons from nitrogen

more stable - electrons can be shared

Describe simple substitutions - pi pi stacking

• Aromatic and heteroaromatic rings

• Planar and hydrophobic

• Interact with flat hydrophobic areas in receptors

What substitution would you do for aromatics?

• Replace with a non-aromatic structure, e.g. cyclohexane

• Weakens binding interactions as less is in contact

• May change shape sufficiently to change ‘fit’