D2 - How do drugs work Flashcards
1
Q
drugs are
A
Drugs - small molecules that bind to a large biological molecule - macromolecule
- Ligands - molecule that binds to another molecule (or ion) - Biological macromolecule is usually the target - Not all drugs work this way - Some drugs neutralise toxins - Large biological molecular target - usually small compared to their target - Some drugs - proteins and antibodies - large molecules being used as drugs
2
Q
Lipids
A
Lipids - not very large, create assemblies eg. Cell membranes - which behave as one large molecule
- Drugs acting on targets inside a cell have to get through a cell membrane - Cell membrane has a hydrophobic interior - Water doesn’t pass passively through a cell membrane - Charged molecules don’t pass through a cell membrane
3
Q
Carbohydrates
A
- Polymers of carbohydrates
- Usually attached to proteins or lipids
- Surface of cells is adorned with carbohydrates - surface is covered
- Glycoproteins, glycosphingolipids (glycoconjugates)
4
Q
Nucleic acids
A
- RNA and DNA
- Anti cancer drugs interact with this
5
Q
proteins
A
- 4 types ○ Transporters § Transport molecules eg. from one side of a cell membrane to the other ○ Structural § Give structure to the inside of a cell § Collagen ○ Enzymes § Catalyse chemical reactions ○ Receptors § Involved in chemical signalling § Regulate processes
6
Q
Induced fit
A
- Drugs and macromolecular targets are conformationally flexible - Macromolecule in particular
○ Adopting different shapes through rotation about single bonds
○ Drug is also conformationally flexible
○ Some reorganisation of target structure upon binding- Maximises binding interactions - lowers energy of complex formed
- Change in shape of macromolecule - important to pharmacological effect - especially when the target is a receptor
- Change in shape of drug as well
7
Q
Molecular recognition
A
- Drugs usually bind their targets selectively through molecular recognition - complementary non-covalent binding interactions (intermolecular forces)
○ Some drugs form covalent bonds - but the binding process usually begins with non-covalent forces - this is rare
○ One molecule recognising another and then forming a complex
○ Process is reversible - binding can occur and than disassociate again
8
Q
Binding regions
A
- Drug has functional groups that has complimentary interaction with binding site
- Needs to be complementarity of
○ shape of the molecule and binding site
○ Charge distribution - how the electron density is distributed in the molecule - Binding site - pocket or cleft in surface of protein
- Needs to be complementarity of
9
Q
Part of the drug sticking out from the binding site
A
- Improves pharmacokinetic properties eg. Water solubility, permeate cell membrane, prevent metabolism
- Pharmacophore - the part that is involved in binding
The combined features of a drug that binds to a target and causes biological effect
- Pharmacophore - the part that is involved in binding
10
Q
Energetics of binding process
A
- Equilibrium process
- Position of equilibrium will depend on the difference in free energy of the complex and free molecules
- Occurring in solution - solvated in water molecules
- Dissociation constant
11
Q
Difference in free energy
A
- Made up of two components
○ Enthalpy
○ Entropy
12
Q
Ionic
A
- Longest range/occurs over the longest distance
○ Important as drug enters the binding site- Drugs and targets are moving around through Brownian motion
- Collisions occur frequently in cells
- Eg. Drug positive and target negative charge - honing in on binding site
- Strength of interaction is inversely proportional to the target
- Ion pairs are non-directional in binding
- Proteins involving metals have directional binding
○ Because the nature of the interaction involves the overlap of a lone pair of electrons with an empty orbital in the metal ion
○ Orbitals have a defined shape - binding is directional
Ionic interactions are weak when there are polar molecules around - eg. Water
If the interaction happens in a hydrophobic pocket of a protein - stronger
13
Q
- Basic Amino acids
A
○ React with a proton in neutral form and form positive charged species
- Acidic amino acid residues - give up proton at physiological pH eg. Aspartate, glutamate - Backbone of DNA and RNA is negatively charged - Polar headgroup of phospholipid making up lipid bilayer of a cell membrane
14
Q
Ionisable functional groups in drugs
A
- Either have a permanent charge or can ionise at ph 7
- Carboxylic acids and amines
- Carboxylic acids
○ Ibuprofen - carboxylic acid
○ Advil - absorbed more rapidly - sodium salt of ibuprofen - dissolves faster in water
○ Equilibrium determined by pH of blood
§ Carboxylic acid present as carboxylate
§ Improved water solubility
§ Likely that there will be ionic interaction with target
○ Non-ionised form could allow drug to get through cell membrane
○ Once inside a cell, can revert back to deprotonated form - Amines
○ pseudoephedrine hydrochloride (Sudafed)
○ Can have a reduction reaction and be made to methamphetamine
○ Form that predominates at ph 7 is ionised form
§ Protonated form has better water solubility and can take part in ionic interactions
Deprotonated form will be important for getting through a cell membran
15
Q
not ionisable functional groups
A
- Amides and alcohols are not ionised at pH 7
○ Amides have a nitrogen atom with a lone pair of electrons
§ Get delocalised onto carbonyl oxygen- Phenols and anilines are predominantly unionised
Phenols are more acidic then alcohols but not enough to be deprotonated
- Phenols and anilines are predominantly unionised
