Optimising Drug Structure

Question 1

What to identify when designing a new drug from a natural ligands or new lead compound

Answer 1

Types of interactions possible
Structural features that are important
Pharmocaphore

Question 2

What is a pharmocaphore

Answer 2

Defines the atoms and functional groups required for a specific pharmacological activity, and their relative positions in space”

Question 3

For a drug to fir into target protein site it must:

Answer 3

Fit into the site
Be held in place by complimentary binding interactions - more biding interactions the tighter it will bind

Question 4

If it is greatly bound then less…

Answer 4

Less drug needed and less costs

Question 5

Intermolecular binding interactions

Answer 5

Ionic
Hydrogen
Van der waals
Hydrophobic
Pi pi

Question 6

Ionic bonds :

Answer 6

Strongest
Between opposite charges
Strength is inversely proportional to the distance between the 2 groups

Question 7

Negatively charged FG’s

Answer 7

Can be deprotoated

• carboxylic acids
• sulfonic acids
• phosphates

Question 8

Ositively charged FG’s:

Answer 8

Can be pronated

H3N-R

Any N containing mol with an avalible lone pair to pick up a proton

Question 9

Hydrogen bods

Answer 9

Weaker than ionic but stronger than van der waals

Place betwen elector define int H and alavalible lone pai on heteroatom

HBA and HBD

Question 10

HBD’s

Answer 10

Alcohol
Thrill
Amines

Question 11

HBA’s

Answer 11

N O or S heteroatoms

Amine, alcohol, ester, thinly, ether, carboxylic, phosphates

Question 12

Van der waals

Answer 12

Very weka

Between hydrophoic regions of drug and target
Drug mst be close to binding region for interaction to occur

Question 13

Pi pi stacking

Answer 13

Non covalent interactions between aromatic rings containing pi bonds

Best overlap is when rings are on top of each other and a little of set

Very common

Question 14

What are the binding roles of alcohols and phenols

Answer 14

Often used in H bonding

O is acceptor and H is donor

Question 15

Bindin roles of aromatic rings

Answer 15

To test importance we replace it with a cyclohexane ring o is no longer flat and may not bind as well

Question 16

Binding role of ketones and aldehydes

Answer 16

Carbonyl is planar and interacts as HBA

To test ipoartannce:
- reduce carbonyl to alcohol
- Changes the geometry to tetrahedral
- weakens H binding and dipole-dipole
Could also replace C=O with a CH2 group to see if HBD groups are important

Question 17

Binding roles of amines

Answer 17

Protonated at physiological pH (7)

• it’s ionised and cannot act of HBA but can act as HBD and form strong H bonds

To test importance:
- convert to amide
- prevents N acting as HBA as the lone pair will interact with neighbouring carbonyl group
- also prevent protonated of N = no ionic interactions

Question 18

Binding role of carboxylic

Answer 18

Can act as HBD and HBA

Question 19

Binding role of esters

Answer 19

HBA only

Question 20

What is a struture activity relationship SAR

Answer 20

Aims to discover which parts of the molecule are important for biological activity

Question 21

Simple substitution

Answer 21

Varying substituents
Remove the group
Bioisosteres Structural simplific

Question 22

Structural extension

Answer 22

Chain extension
Ring expansion/contraction Ring fusion
Ring variation

Question 23

Alter 3D shape

Answer 23

Stereochemistry
Rigidification
Conformational blockers

Question 24

Lipinskis rule

Answer 24

Molecular weight less than 500
No more than 5 HBD
No more than 10 HBA
LogP less than +5

Question 25

How does hydrophobicity affect drug behaviour

Answer 25

How readily a drug crosses cell membranes How a drug interacts with a protein receptor

Question 26

Extension of the structure

Answer 26

* Lead compound wont necessarily hit all of the possible binding sites in a receptor * Could add extra functional groups to the lead in order to probe for extra binding interactions * Often used to find extra hydrophobic regions * Frequently used strategy to turn agonists into antagonists

Question 27

Chain extension

Answer 27

Some drugs have two important binding groups linked together by a chain, in which case it is possible that the chain length is not ideal for the best interaction. Therefore, shortening or lengthening the chain is a useful tactic to try.

Question 28

Ring variations

Answer 28

* varying the rings in drug structures can lead to improved binding * In particular, changing an aromatic ring to a heteroaromatic ring can often give new binding interactions

Question 29

Bioisoster

Answer 29

Group that can be used to replace another group while retaining the desired biological activity Often used to replace a FG that is important for target binding but it also problematic

Question 30

Simplification of the structre

Answer 30

Removal of chiral carbons is a benefit ie statins

Question 31

Rigidification

Answer 31

To lock a compound into active site Can be used to increase activity Can be ridgified by adding rigid FGs’ like double bonds, alkynes, amides or aromatic rings