12 Chemical basis of pharmacology

Question 1

Hydrophilic interactions

Answer 1

Can form hydrogen bonds with water molecules (tend to dissolve in water)

Typically polar or ionic (have positive and negative region) - allowing them to interact with other polar charged molecules like water

Examples - salts / alcohols / sugars / AA with polar side chains

Question 2

Hydrophobic interactions

Answer 2

Tend to not dissolve in water and aggregate together in aqueous environments to minimise exposure to water

Usually non-polar (uncharged) so lack the ability to form hydrogen bonds with water

Examples - lipids (FA and oils) / hydrocarbons / AA with non-polar side chain

Question 3

Key differences between hydrophobic and hydrophilic interactions

Answer 3

Hydrophilic interactions = attraction between water molecules and polar or charged molecules
Hydrophobic interactions = exclusion of non-polar molecules from water

Hydrophilic substances dissolve in water but hydrophobic substances do not

Question 4

Types of drug targets - enzymes

Answer 4

Proteins that catalyse biochemical reactions, drugs can inhibit or activate enzymes

Question 5

Types of drug targets - receptors

Answer 5

Proteins that receive signals (ligands) from other molecules (such as neurotransmitters and hormones)

Question 6

Types of drug targets - ion channels

Answer 6

Proteins that allow ions to pass across cell membranes

Question 7

Types of drug targets - transporters

Answer 7

Protiens that move substances across cell membranes

Question 8

Types of drug targets - nucleic acids

Answer 8

Drugs can target DNA or RNA to affect gene expression

Question 9

Chemistry behind drug-target interaction

Answer 9

The drug typically binds to a target protein via NON-covalent interaction (such as hydrogen, VDW, ionic and hydrophobic)

The affinity (how strongly a drug binds to its target) is a critical determination of the drugs potency

Question 10

Some AA can form cross links…

Answer 10

…cysteine can cross-link with another cysteine through an interaction between the -SH groups (important for protein folding)

Question 11

Drugs are usually…

Answer 11

Organic and cyclic

Question 12

Computer-aided drug design (CADD) - what does it do

Answer 12

Helps visualise 3D images of drug molecules and their receptors

Question 13

CADD - how can new drugs be designed

Answer 13

New drugs can be designed based on the predicted chemical interaction with its target

Question 14

CADD overview

Answer 14

use of computational methods to discover, design, and optimize drugs by simulating their interactions with biological targets

This approach accelerates the drug discovery process and reduces costs

Question 15

Structure activity relationship (SAR) definition

Answer 15

Relationship between the chemical or 3D structure of a molecule and its biological activity

Understanding SAR helps in designing new drugs or improving existing drugs

Question 16

SAR - key concepts

Answer 16

1. Functional groups
2. Molecular size and shape
3. Lipophilicity
4. Pharmacophore

Question 17

SAR - functional groups

Answer 17

Drastically change biological activity

Eg. Adding or removing a hydroxyl group can increase or decrease solubility, affecting how a drug is absorbed and its potency

Question 18

SAR - molecular size and shape

Answer 18

Drugs size and shape must be complementary to the targets binding site for effective interaction

Question 19

SAR - lipophilicity

Answer 19

The lipophilic (fat-soluble) or hydrophilic (water-soluble) nature of a compound affects its ability to cross cell membranes

SAR studies aim to optimise these properties for better bioavailability and efficacy

Question 20

SAR - phamacophore

Answer 20

Pharmacophore - minimal molecular arrangement of atoms or groups responsible for the drugs biological activity

SAR studies identify the key components of the pharmacophore that can be optimised

Question 21

SAR - application in drug design

Answer 21

Optimisation of leading compounds - helps medical chemists modify existing compounds to enhance their effectiveness and reduce side effects

Design of novel compounds - SAR aids the prediction of the effects of chemical modifications on the biological activity

Question 22

Chemical transmission (neurotransmission) overview

Answer 22

refers to the process by which signals are transmitted between neurons and other cells through the release of neurotransmitters at synapses

Question 23

Stages of chemical transmission

Answer 23

1. Action potential
2. Neurotransmitter release
3. Neurotransmitter binding
4. Signal propagation
5. Neurotransmitter removal

Question 24

1. Action potential

Answer 24

Electrical impulse travels down the axon of a neurone to the axon terminal

Question 25

2. Neurotransmitter release

Answer 25

Action potential caused voltage gated calcium channels to open leading to an influx of ca2+ ions, which triggers vesicles containing neurotransmitters to fuse with the presynaptic membrane, releasing neurotransmitters into the synaptic cleft

Question 26

3. Neurotransmitter binding

Answer 26

The neurotransmitter crosses the synaptic cleft and binds to specific receptors on post synaptic neurone or other target cells

Question 27

4. Signal propagation

Answer 27

Binding of the neurotransmitter leads to changes in the postsynaptic cell, such as opening ion channels, which may initiate an action potential or cause a change in the cells function

Question 28

5. Neurotransmitter removal

Answer 28

Neurotransmitter is cleared from the synaptic cleft by reuptake into the presynaptic neurone, enzymatic degradation or diffusion away from the synapse

Question 29

Types of neurotransmitter (3)

Answer 29

1. Excitatory
2. Inhibitory
3. Modulatory

Question 30

Excitatory neurotransmitters

Answer 30

Increase the likelihood of a postsynaptic action potential

Question 31

Inhibitory neurotransmitters

Answer 31

Decrease the likelihood of a postsynaptic action potential

Question 32

Modulatory neurotransmitters

Answer 32

Regulate the activity of excitatory or inhibitory neurones

Question 33

Examples of drugs affecting chemical transmission

Answer 33

Antidepressants (SSRIs) - Block the reuptake of serotonin, increasing its availability in the synaptic cleft

Benzodiazepines - Enhance the effect of GABA, promoting inhibition of neuronal activity

Caffeine - Blocks adenosine receptors, promoting wakefulness.

Question 34

If a drug is hydrophilic it’s less likely to be absorbed by the body…

Answer 34

…as it cant easily diffuse across the membranes, likely to not disperse as well nor cross tissue barriers

Hydrophilic drugs tend to be rapidly excreted from the body

Question 35

Penicillin - mechanism of action

Answer 35

bactericidal / inhibits bacterial cell wall synthesis (prevents peptide cross links and inhibits bacterial transpeptidase / beta-lactam ring and carboxylic acid group essential for activity

Question 36

Penicillin - stability

Answer 36

unstable in acid (stomach) / poorly absorbed

Beta-lactamases - enzymes produced by some bacteria —> can be responsible for penicillin resistance

Question 37

Penicillin - SAR

Answer 37

Varying structure of penicillin can change its properties

Question 38

The neurotransmitter at all ganglia is…

Answer 38

Acetylcholine

Question 39

The neurotransmitter at (nearly) all sympathetic neurone factor junctions is

Answer 39

Noradrenaline

Question 40

Physical regulators

Answer 40

Increase sympathetic nerve drive

Noradrenaline release

Beta-adrenal receptor activation