lecture I: drug-target interactions Flashcards
Affinity
The affinity of a drug for a receptor is a measure of how strongly (tightness) that drug binds to the receptor.
A compound with high affinity does not necessarily have high efficacy
→expressed as the equilibrium dissociation constant KD in M (mol/L)
Efficacy
Efficacy is a measure of the maximum biological effect that a drug can produce as a result of receptor binding.
A compound with high affinity does not necessarily have high efficacy
It is possible for a drug to be potent (i.e. active in small doses) but have a low efficacy
Potency
Potency of a drug refers to the amount of drug required to achieve a defined biological effect
→the smaller the dose required, the more potent the drug
It is possible for a drug to be potent (i.e. active in small doses) but have a low efficacy
Target
Any cellular macromolecule that a drug binds to initiate its effect.
EX: proteins (enzymes, receptors, transport proteins), DNA (nucleic acid)
Drug
A chemical substance that interacts with a receptor to produce a
physiologic effect.
→all drugs are chemicals but not all chemicals are drugs
Target + Drug
The ability of a drug to bind to a receptor is mediated by its chemical structure allowing interactions with the complementary surfaces on the receptor and eliciting intermolecular forces.
→shapes plays a role and facilitates IMFs
Pharmacodynamics
Pharmacodynamics is the study of how a drug binds to its target binding site and produces a pharmacological effect.
→”what the drug does to the body”
Pharmacokinetics
Pharmacokinetics is the study of how a drug is absorbed, distributed, metabolized, and excreted (ADME).
→”what the body does to the drug”
Binding
The interaction of a drug with a macromolecular target.
→dynamic, flexible, constant movement
→different modes of how a drug can interact with its target exist, some are better than others
Binding pocket
3D structure within the target, in which drugs fits and bind.
→usually a specific area of the macromolecule where binding takes place
Pharmacophore
The drug’s steric (shape and position) and electronic features (chemical functional groups) that are necessary to ensure the interactions with a specific biologic target and trigger (or block) a biologic response
Active site
Catalytic active site of an enzyme where reaction happens; amino acids involved in catalysis and substrate binding.
→not necessarily the binding pocket
Factors influencing binding
- IMFs (and thus affinity)
→the more IMFs, the tighter
→the more energy in the bond, the tighter
→you need to find the sweetspot because you don’t necessarily want it to bind too tight to allow for proper drug dosing - pH
→cellular location matters (different aa side chains are protonated differently at different pHs) - water shell
→has to be removed for proper interaction
Drug-target complex examples
- Valsartan & AT1R
- Gleevec & BCR-Abl kinase (at the DFG loop → if the loop is in or out, it will alter Gleevec’s ability to bind)
Models of drug-target binding
- Lock & key
- Induced fit
- Conformational selection / selected fit
Lock & key binding
To exercise an action a ligand must fit into a protein binding cavity like a key into a keyhole.
no longer very relevant, induced fit model makes more sense
Induced fit binding
The proximity of a drug to its target induces conformational changes that favour their interaction.
Conformational selection / Selected fit binding
Conformational changes occur prior to the binding of a ligand. Ligands “select” and stabilize certain sets of conformations, thus shifting equilibrium towards the “active conformation”.
→multiple conformations of a protein can exist where the drug can bind
Cryo-EM
Cryogenic electron microscopy
A cryomicroscopy technique applied on samples cooled to cryogenic temperatures.
Recent advances in detector technology and software algorithms have allowed for the determination of biomolecular structures at near-atomic resolution. This has attracted wide attention to the approach as an alternative to X-ray crystallography or NMR spectroscopy for macromolecular structure determination without the need for crystallization.
→allows us to determine the type of binding and fits!
IMFs
Intermolecular forces
“Tightness” (affinity) depends on the quality and number of intermolecular forces (and thus on how well complementary surfaces fit).
Biologically relevant IMFs
- Ionic interactions
- Dipole-dipole interactions (+ ion-dipole interactions)
- Hydrogen bonding
- Van der Waals interactions
- 𝜋-𝜋 stacking
- Repulsive forces
- Water shell
→Some drugs react with the binding site and become permanently attached via a covalent bond, but most interact through weaker IMFs
→None of these bonds is as strong as the covalent bonds that make up the skeleton of a molecule, and so they can be formed and then broken again. This means that an equilibrium takes place between the drug being bound and unbound to its target.
covalent bonds are NOT IMFs, but they are still relevant
Covalent bond
- basis of attraction: 2 atoms share a pair of electrons
- energy: 200 – 400 kJ/mol
→a lot used to break apart the 2 atoms - range: 1.0-1.54 Å
- technically not an IMF, since it becomes one entity once the electrons are shared
Ionic interactions
The strongest of the IM bonds and takes place between groups that have opposite charges.
- basis of attraction: cation–anion electrostatic attraction
- energy: 20 - 40 kJ/mol
- range: longer
→if an ionic interaction is possible, it is likely to be the most important initial interaction as the drug enters the binding site
Factors influencing ionic interactions
Dependent on the nature of the environment.
→stronger in hydrophobic environments than in polar environments
(the binding sites of macromolecules are more hydrophobic in nature than the surface and so this enhances the effect of an ionic interaction)
→pH
(causes drug/target to either be charged or not due to aa side chains)
