Ian Eggleston - Intro to QSAR Flashcards
What are the 5 steps in the drug discovery process?
1) Find target
2) Validate biology
3) Discover a lead
4) Determine/refine SAR
5) Optimise the lead
What are leads?
Prototype chemical structures/series of structures with the desired biological activity
Where can leads come from? (6)
1) Natural products
e. g morphine, aspirin, quinine
2) Synthetic compound collections
e. g screen when found new target
3) Existing drugs
e. g penicillins - variation on a theme (lots of diff types)
4) Natural receptor ligands, enzyme substrates
e. g adrenaline & noradrenaline were starting points for salbutamol, can also use to design antagonists e.g histamine was lead for H2 antag Cimetidine
5) Rational (computer aided) design
e. g Crystallise receptors or enzymes to see structure of protein and binding site and then use mol modelling to study and design molecules to fit into it (de novo design)
6) Combinatorial synthesis
e. g automated solid phase procedure, produce as many structures as possible in short time - leaving a mixture of compounds - one may work!
When given a lead compound, how do we determine which groups or structural features are important for binding or biological activity?
- Think of as a knight going into battle
- What groups are important for activity and protection?
- Find out by removing these groups in a stepwise manner and see how activity is affected
- Can also add different groups to see alterations in activity
e.g Morphine - can remove 3 and 6 hydroxy groups and see how activity is altered! Or mask the groups by making more lipophilic and see what effect this has
What is the rationale behind Structure Activity Relationship?
- if change structure and activity drops
- if change structure and little effect
- if change structure and enhanced activity
- drop in activity means group important for binding has been altered
- little effect in activity means group/part of molecule was not important for binding
- if activity enhanced then an additional interaction with the target may have been found e.g H bond, VDW, Ionic
What kind of interactions between a drug molecule and target may be important? (5)
1) Ionic
2) H bonding
3) Van der Waals
4) Dipole-Dipole
5) Covalent
How can an alcohol or phenol group on the drug molecule be manipulated to test for presence of a certain type of interaction with a target
- Alcohol and phenol groups possess H atoms that are HBDs and O atoms that are HBA
- This means the drug molecule may interact though H BONDING with the target
- By REMOVE the potential for H BONDING - see if important for the drugs action
- Remove H bonding potential by synthesising an ESTER by ACETYLATION or methyl ether analogue
- The methyl on an ether group will hinder any H bond accepting properties of the O and the H bond donating properties will have been lost by removal of the H
- The extra ACYL group on the ester will HINDER the original HBA properties of the O and the HBD properties lost by removal of the H
- If doing this reduces activity then we know H bonding is important for the drugs activity
How can amines be manipulated to test for presence of certain type of interactions with target?
- Amines are HBDs if 1ry or 2ry (due to H atoms)/HBAs (due to lone pair) when unionised
- Aromatic amines are only HBD as the lone pair is not available to accept H atom as it interacts with ring
- Amines can interact by ionic bonding when ionised as it can become protonated when it interacts with its target binding site - only HBD properties here
- Synthesise an amide analogue to see if ionic or H bonding interactions taking place
- Prevent N acting as an HBA as N lone pair interact with carbonyl group ALSO prevent protonation of N and rules out ionic interactions
- Tertiary amide lacks N-H properties and can see if involved as H bond donor, Secondary amides do not act as HBD as well due to steric bulk of acyl group so hinder donating properties
How can acids be manipulated to test for presence of certain type of interactions with target?
- Acids can act as HBA or HBD
- C=O = HBA
- C-OH = Weak HBA on O and HBD on H
- Carboxylate ion = ionic interactions/strong HBA
- Can synthesise ester, 1ry amide, 1ry alcohol or ketones
- None of these groups can ionise so rule out ionic bonding if no change in activity
- 1ry alcohol can see if C=O important for HBA as OH weak HBA and good HBD properties
- Ester/amide can see if -OH important for HBD as only HBA properties
What interactions with targets can aromatic rings possess and why?
- VDW interactions as they are planar, hydrophobic structures
- Not very bulky compared to cyclohexane ring which may not be able to interact due to H atoms acting as buffers
Why might an alkene be able to interact with hydrophobic regions present on a target?
Why might saturated molecules find this more difficult?
How can we test whether these properties of alkenes are important for binding with the target?
- Alkenes are more planar and hydrophobic so can interact with hydrophobic regions through VDW forces
- Saturated molecules are bulkier and may not be able to approach the binding region as easily due to steric hinderance
- Can reduce the alkene to make it a saturated, bulkier molecules which may hinder it’s ability to interact with VDW forces with the target. If activity it reduced then we know this property of the alkene is important for it’s activity
- What property of alkyl groups enable them to bind with targets?
- How can we test whether these interactions are important for activity?
- They are hydrophobic and can bind with hydrophobic regions of binding sites through VDW forces
- We can change the size or shape of the molecule to see whether steric hinderance will prevent the VDW forces
- If activity is reduced after this change then we know that the VDW interactions are important for the drugs activity
What is a pharmacophore of a drug?
- The functional groups required for biological activity and their relative positions in space
What are the principles and aims of the QSAR (Quantitative Structural Activity Relationship) approach?
- To identify and quantify the physiochemical properties of a drug and investigate whether they affect its biological activity
- An equation is drawn up to quantify the relationship to allow medicinal chemists to say that a certain property has a role in the drugs pharmacokinetics/mechanism of action
- To derive a mathematical formula that relates the biological activity of a series of compounds to particular physiochemical properties
If an equation can be drawn up using the QSAR approach, what outcome will this have?
- Med chemists can be sure that certain physiochemical properties of a drug play a role in it’s pharmacokinetics/mechanism of action
- This means that activity of a novel agent can be predicted in advance which can reduce how many compounds need to be made.
- It can help to highlight new leads with desirable physiochemical properties
