12 Chemical basis of pharmacology Flashcards
Hydrophilic interactions
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
Hydrophobic interactions
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
Key differences between hydrophobic and hydrophilic interactions
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
Types of drug targets - enzymes
Proteins that catalyse biochemical reactions, drugs can inhibit or activate enzymes
Types of drug targets - receptors
Proteins that receive signals (ligands) from other molecules (such as neurotransmitters and hormones)
Types of drug targets - ion channels
Proteins that allow ions to pass across cell membranes
Types of drug targets - transporters
Protiens that move substances across cell membranes
Types of drug targets - nucleic acids
Drugs can target DNA or RNA to affect gene expression
Chemistry behind drug-target interaction
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
Some AA can form cross links…
…cysteine can cross-link with another cysteine through an interaction between the -SH groups (important for protein folding)
Drugs are usually…
Organic and cyclic
Computer-aided drug design (CADD) - what does it do
Helps visualise 3D images of drug molecules and their receptors
CADD - how can new drugs be designed
New drugs can be designed based on the predicted chemical interaction with its target
CADD overview
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
Structure activity relationship (SAR) definition
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
SAR - key concepts
- Functional groups
- Molecular size and shape
- Lipophilicity
- Pharmacophore
SAR - functional groups
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
SAR - molecular size and shape
Drugs size and shape must be complementary to the targets binding site for effective interaction
SAR - lipophilicity
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
SAR - phamacophore
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
SAR - application in drug design
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
Chemical transmission (neurotransmission) overview
refers to the process by which signals are transmitted between neurons and other cells through the release of neurotransmitters at synapses
Stages of chemical transmission
- Action potential
- Neurotransmitter release
- Neurotransmitter binding
- Signal propagation
- Neurotransmitter removal
- Action potential
Electrical impulse travels down the axon of a neurone to the axon terminal
- Neurotransmitter release
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
- Neurotransmitter binding
The neurotransmitter crosses the synaptic cleft and binds to specific receptors on post synaptic neurone or other target cells
- Signal propagation
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
- Neurotransmitter removal
Neurotransmitter is cleared from the synaptic cleft by reuptake into the presynaptic neurone, enzymatic degradation or diffusion away from the synapse
Types of neurotransmitter (3)
- Excitatory
- Inhibitory
- Modulatory
Excitatory neurotransmitters
Increase the likelihood of a postsynaptic action potential
Inhibitory neurotransmitters
Decrease the likelihood of a postsynaptic action potential
Modulatory neurotransmitters
Regulate the activity of excitatory or inhibitory neurones
Examples of drugs affecting chemical transmission
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.
If a drug is hydrophilic it’s less likely to be absorbed by the body…
…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
Penicillin - mechanism of action
bactericidal / inhibits bacterial cell wall synthesis (prevents peptide cross links and inhibits bacterial transpeptidase / beta-lactam ring and carboxylic acid group essential for activity
Penicillin - stability
unstable in acid (stomach) / poorly absorbed
Beta-lactamases - enzymes produced by some bacteria —> can be responsible for penicillin resistance
Penicillin - SAR
Varying structure of penicillin can change its properties
The neurotransmitter at all ganglia is…
Acetylcholine
The neurotransmitter at (nearly) all sympathetic neurone factor junctions is
Noradrenaline
Physical regulators
Increase sympathetic nerve drive
Noradrenaline release
Beta-adrenal receptor activation
