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
16
Q
Hydrogen bonding
A
- Properties of water
- Hydrogen shared between x and y
- X is very electronegative with lone pairs of electrons
- Directional
- Hydrogen bonds arises when there is
○ Orbital with lone pair of electrons - hydrogen bond acceptor
○ Electronegative atom - oxygen or nitrogen with a covalent bond to hydrogen (sigma bond)
○ Anti bonding orbital will be associated with the sigma bond
17
Q
Salt bridges
A
- Negatively charged functional group with lone pair of electrons
- Between drugs, between protein residues, aspartate and glutamate residues holding proteins together
18
Q
Dispersion forces
A
- Occur between all molecules
- Most important in hydrophobic parts of molecules (non polar)
- Weakest type of non covalent interaction
- In a polar environment
○ dispersion forces between drug and water molecules are negligible
○ Dispersion forces between hydrophobic molecules are significant - Weak - needing close contact between molecules
- Shape complementarity is necessary
19
Q
Water
A
- Binding interactions occurring in a polar solvent
- Drug and protein molecule are solvated
- Forming hydrogen binds with drugs and binding site
- Ionic interactions and hydrogen bonds form with water - inhibit it forming at the binding site - costs energy because hydrogen bonds are favourable interactions
○ Interactions with water have to be broken to create interaction with binding site
○ Less likely to be energetically favourable
20
Q
Increasing heart rate
A
- Chronic low heart rate
- Endogenous molecules - hormones that increase heart rate - eg. Adrenaline
○ Too many side effects
○ CNS effects
○ Constricts arteries and veins around the heart - Isoprenalin
○ A1 causes vasoconstriction
○ B adrenoceptor in the heart increases heart rate
○ Isoprenalin
§ Substitution of a methyl to an isopropyl
§ Isopropyl group has stearic clash with receptor pocket of A1 - doesn’t fit in the binding site - no longer causes vasoconstriction - creating selectivity of the target
- Endogenous molecules - hormones that increase heart rate - eg. Adrenaline
21
Q
Endogenous molecules - hormones that increase heart rate - eg. Adrenaline
A
○ Too many side effects
○ CNS effects
○ Constricts arteries and veins around the heart
22
Q
- Isoprenalin
A
○ A1 causes vasoconstriction
○ B adrenoceptor in the heart increases heart rate
○ Isoprenalin
§ Substitution of a methyl to an isopropyl
§ Isopropyl group has stearic clash with receptor pocket of A1 - doesn’t fit in the binding site - no longer causes vasoconstriction - creating selectivity of the target
23
Q
High energy conformation
A
- Maybe in protein
- Molecules are flexible - rotation about single bonds
- Unstable
- Results from repulsion - bringing bonds too close together and the electron density causes repulsion
24
Q
ACE inhibitors
A
- ACE = angiotensin-converting enzyme
- Used for treatment of high blood pressure
- Lowers energy of molecule by creating stronger ionic interaction
- Cilazapril
25
Q
Entropy
A
- Measure of disorder
- Disordered state is more energetically favourable
- More negative - more stable the complex is
- Negative entropy change - does not favour formation of complex
- Going from two molecules to one - goes against entropy (double degree of freedom with two separate molecules)
- Entropy must be lost when a drug binds its target - energy is lost
26
Q
If a drug molecule is conformationally flexible
A
- When it binds, it adopts a more restricted conformation - loss of entropy due to fewer degrees of freedom (flexibility)
- Loss of entropy, not energetically favourable
- Solution: Start with a rigid molecule to begin with - has less entropy to lose when binding to the target, less energetically unfavourable
○ Aromatic planar rings and double and single bonds increase rigidity
Drugs made rigid -aromatic rings, double and triple bonds
27
Q
Hydrophobic effect
A
- Hydrophobic parts of drugs
- If a drug dissolves in water with a hydrophobic region - water molecules must become more ordered around it
- When alongside a hydrophobic region - loses entropy
- Structured shell of water - loss of entropy
- Hydrophobic binding region on macromolecular target
- When the drug forms a complex - ordered water molecules are released into the solvent - entropy increases - only type of entropy that can increase when a drug binds to a target
- Energetically favourable because binding creates gain in entropy
○ Although some energy is lost by the drug and target binding and forming one entity
○ This is the only way drug binding can create a gain in entropy - When a non-polar molecule is dissolved in water, more structures water-water interactions are formed in the solvent shell to compensate for the weaker interactions between solute and water
- Increased organisation of water molecules around the solvent shell creates a decrease in entropy
- Non-polar surface area is reduced when two molecules come together
○ Favourable entropy of association - Entropy of solvation can be positive or negative
○ Polarity must be balanced in drugs. Fatty drugs have poor water solubility and often off-target effects (side effects/toxicity) - Drug has to be water soluble - cant be too fatty or it doesn’t get absorbed and distributed
- Hydrophobic drugs associated with unwanted side effects
Will stick to other hydrophobic targets
28
Q
- Amphotericin
A
Drugs that target cell membranes
- Cell membranes - polar head groups and hydrophobic interior
- Amphotericin
○ used to treat fungal infections interacts with cell membrane of a fungi
○ Amphoteric - reacts with both acid and base
§ Acidic and basic functional group
○ Amphiphilic - loving and hating water
○ Targets Ergosterol - on the cell membrane of fungi - similar to cholesterol on human cells
§ Ergosterol molecules clump together to form a pore through the cell membrane on the fungi - causes apoptosis
§ Fungal cells have high osmolarity inside the cell
□ Internal pressure
§ Selective for fungal cells because they have ergosterol and we have cholesterol and it does not bind cholesterol
29
Q
Drugs that target DNA
A
- Most commonly used to treat cancer
- DNA bases bind to one another and are stacked on top of one another
- Intercalating agents
○ Have planar rigid structure like DNA bases
○ Hydrophobic core
○ Slip in between DNA bases and causes favourable binding interactions
○ Positively charged functional group that has an ionic interaction with the negatively charged phosphodiester backbone of the DNA - Daunorubicin
○ Binds and intercalates into DNA and changes shape - no longer recognised by enzymes that replicate DNA
○ transcription cannot occur - cancer cannot replicate
30
Q
- Daunorubicin
A
○ Binds and intercalates into DNA and changes shape - no longer recognised by enzymes that replicate DNA
○ transcription cannot occur - cancer cannot replicate
31
Q
Drugs that target proteins
A
- Most common drug targets
- Amprenavir-HIV protease
○ Used to treat HIV to prevent aids
○ HIV-protease - produced by HIV virus
§ If you inhibit this, it stops it from replication
§ Functional as a homodimer
§ Active site - interface between the two proteins
○ Crystal of the protein in complex of the drug
§ Interrogated using x ray crystallography (taking a picture of a molecule)
§ Used to help design this drug - rational drug design
§ Empty site - catalytic site - molecule designed to fit in the site - Interaction between drug and protein
○ Hydrogen bond acceptors on protein - lone electron pairs
○ Drug has hydrogen bond donors
○ Hydrogen bond with alanine and peptide
- Amprenavir-HIV protease
32
Q
amprenavir
A
- Amprenavir-HIV protease
○ Used to treat HIV to prevent aids
○ HIV-protease - produced by HIV virus
§ If you inhibit this, it stops it from replication
§ Functional as a homodimer
§ Active site - interface between the two proteins
○ Crystal of the protein in complex of the drug
§ Interrogated using x ray crystallography (taking a picture of a molecule)
§ Used to help design this drug - rational drug design
§ Empty site - catalytic site - molecule designed to fit in the site
