1 and 2

Question 1

List the Drug Discovery Pathway?

Answer 1

Biology 1 –> HTS –> Med Chem/DMPK –> Biology 2 –> Clinical trials

Question 2

What is HTS and DMPK?

Answer 2

HTS = High throughput Screening

DMPK = Drug Metabolism Pharmacokinetics

Question 3

What is the Pre-clinical stage?

Answer 3

Biology 1, HTS, Med Chem/DMPK and Biology 2

Question 4

Why aren’t all lead compounds used as a drug?

Answer 4

Most lead compounds are unsuitable for clinical use for a variety of reasons:

• Not active enough
• Have serious or undesired side effects
• Not easily administered to patients → not orally active

Question 5

How can we develop drugs from leads?

Answer 5

By changing the structure.

Structural changes to a lead compound often alter pharmacological action and can improve a particular activity or eliminate side effects

Question 6

What do similar molecules tend to have?

Answer 6

Structurally similar molecules tend to have similar properties → neighbourhood behaviour.

E.g. Codeine, Morphine and Heroin

Question 7

What is ‘STRUCTURE-ACTIVITY RELATIONSHIP’ (SAR)?

Answer 7

The correlation of structure with biological activity

Question 8

What is the aim of SAR studies?

Answer 8

• Determine which parts of the lead molecule are essential for biological activity and which parts cause the undesired side effects
• Develop an analogue of the lead compound that has the best combination of therapeutic properties

Identifies all important binding groups in the lead compound - Pharmacophore

Question 9

What is a pharmacophore?

Answer 9

A pharmacophore contains only the relevant groups that interact with a receptor and are responsible for the activity

Question 10

How to use SAR’ s to determine the pharmacophores?

Answer 10

IDENTIFICATION OF A LEAD STRUCTURE

IDENTIFICATION OF POSSIBLE DRUG TARGET BINDING GROUPS

SYNTHESIS OF A SERIES OF ANALOGUES WHERE ONE BINDING GROUP IS REMOVED

TEST ALL ANALOGUES FOR BIOLOGICAL ACTIVITY

IDENTIFICATION OF PHARMACOPHORE

So a single binding group is modified or removed

Question 11

Explain the results of SAR studies?

Answer 11

If bioactivity is much lower after modification we know that functional group is important and all analogues must contain it.

Question 12

What are the three different ways in which a potential binding group can bind to a target?

Answer 12

H-bonding: This is important for groups possessing electron defficient hydrogens, e.g., hydroxyl and amino groups

Ionic binding: Important for groups that can form cations or anions in vivo, e.g., amino groups

Van der Waals / Hydrophobic contacts: Important for hydrophobic groups that can lie close to and interact with hydrophobic groups in a target, e.g., aromatic rings, double bonds

Question 13

What does ligand hydrophobicity and hydrogen bonding give?

Answer 13

Ligand hydrophobicity gives affinity, whereas hydrogen bonding gives specificity.

It is generally accepted that high-affinity ligands bind in low-energy confirmations.

Question 14

What do Biochemical systems exhibit?

Answer 14

Biochemical systems exhibit enthalpy-entropy compensation, where increased bonding is offset by an entropic penalty, reducing the magnitude of change in affinity.

Question 15

Explain how hydroxyl groups are involved in hydrogen bonding?

Answer 15

1. Via the hydrogen atom, by interaction with a carbonyl group (or other lone pair donor) on the receptor
2. Via the oxygen atom by interaction with an electron deficient hydrogen atom on the receptor

Question 16

Explain how a hydroxyl group can be removed?

Answer 16

An hydroxyl group can be totally removed by conversion to a mesylate or tosylate followed by reduction with LiAlH4.

Question 17

What are amino groups involved in and how is this prevented?

Answer 17

Amines are involved in H-bonding and ionic bonding to groups on the receptor.

Conversion of the amine to an amide will prevent involvement of the lone pairs in hydrogen bonding, and will also prevent ion formation.

Question 18

How are Tertiary amines dealkylated? And why?

Answer 18

This is usually done using cyanogen bromide – the von Braun reaction.

Because they have no hydrogen attached, so hydrogen bonding cannot happen as hydrogen is needed for this bonding to occur.

Question 19

What are Aromatic rings involved in?

Answer 19

Usually involved in van der Waals interactions with hydrophobic parts of a target site.

Aromatic rings can interact with flat hydrophobic parts of a receptor → π-π stacking.

Question 20

Where are VDW strongest?

How is this weakened in Aromatic rings?

Answer 20

Van der Waals interactions are cumulative and are strongest between moieties that can approach each other closely.

The aromatic ring may be hydrogenated to a cyclohexane - the structure is no longer flat and van der Waals interactions with the receptor will now be weaker.

Question 21

What are double bonds involved in?

What weakens this?

Answer 21

Van der Waals interactions with hydrophobic regions of a receptor.

Reduction will weaken the interaction as the alkane cannot approach the receptor surface as closely.

Question 22

What are ketones involved in?

How does this work and how is this interaction weakened?

Answer 22

H-bonding or dipole-dipole interactions with the target.

The ketone will align to interact with a dipole moment in the target.

Reduction to an alcohol will weaken both types of interaction. The geometry and hence alignment of the functional group will change.

Question 23

What are amides involved in?

How is this weakened/disrupted?

Answer 23

H-bonding of the carbonyl oxygen.

Reduction will disrupt H-bonding involving the carbonyl oxygen.

Question 24

What is an Isostere?

Why are they important?

Answer 24

An atom or group of atoms having identical numbers of outer shell electrons.

Replacement of a potential binding group with a classical isostere is a useful way of determining whether it is important or not.

Question 25

What are non-classical isosteres?

Answer 25

Isosteres that differ by one parameter, e.g., size or electronegativity

Question 26

What are the different isosteres?

Answer 26

• SH, NH2 , CH3 are isosteres of OH
• S, NH, CH2 are isosteres of O
• Replace OH with CH3 can be used to determine if H-bonding is taking place
• Replace OH with NH2 , H-bonding remains