1. Drug-Target Interactions Flashcards
what is a target?
any cellular macromolecule that a drug binds to –> enzyme, receptor, protein, or DNA
what is a drug?
chemical substance that interacts with target to produce beneficial physiological effect
what mediates the ability of a drug to bind its receptor?
drug chemical structure interacts with complementary surfaces on the target to elicit intermolecular forces
what is the difference between a drug and chemical?
both bind at target but drug produces biologically beneficial effect
what is a binding pocket?
3D structure within the target in which the drug fits and binds (i.e. AA that the drug interacts with)
what is a pharmacophore?
the drug’s steric (shape and position) and electronic features (chemical functional groups) that are necessary to ensure the interactions with target trigger/block a biologic response
ENZYMES vs RECEPTOR
- Enzyme has catalytic active site where reaction occurs
- Receptor has ligand binding site
what are the 3 models of drug-target binding? which are possible?
- lock and key
- induced fit
- conformational selection/selected fit
2 and 3 are possible
describe the lock and key
less accurate now –> perfect match between drug and target
describe the induced fit model
drug approximates target, then when drug is present, the target changes conformation to allow binding
- favoured by entropy
- ex. Gleevec
describe the conformational selection/selected fit model
target is constantly changing conformation (due to enzymes or random thermal motion) and only at specific conformation will the drug bind
what is affinity?
measure of the TIGHTNESS with which a drug binds to the receptor
what does affinity depend on?
quality and number of intermolecular forces
besides affinity, what 2 other factors influence binding?
- water shell
- pH
describe covalent bonds and their energy
no affinity involved –> they are 1 molecule, there is no dissociation constant
highest energy!
describe ionic interactions and their length
not very specific –> just cation-anion attraction
pretty long bonds
what is an example of ionic interaction?
C-terminus binding N-terminus
describe H bonds and their length
Electron-deficient hydrogen is covalently bonded to an electronegative atom (O, N, F) and then binds electron-rich heteroatom
longer bond so less energy –> easier to break the bond
what is a hydrogen bond donor? what is a hydrogen bond acceptor?
donor: H covalently bonded to O, N, F
acceptor: electron-rich atom on a functional group
describe why hydrogen bond donors form
hydrogen is covalently bonded to an electronegative atom which has a greater attraction for electrons, so the electron distribution in the bond gives H a slight positive charge
what are some examples of hydrogen bond acceptor?
C=O, C=N-C, C-O-C
what is an example of hydrogen bond donor?
OH
what is an example of a hydrogen bond donor and acceptor?
NH3 –> can act as either donor or acceptor in different cases
when do we see hydrogen bonds in biomolecules?
- water shell –> btwn OH or C=O and water
- secondary protein structure –> btwn peptide groups in polypeptides
- DNA base pairing
what are some examples of amino acids that are hydrogen bond acceptors only?
glutamic/aspartic acid
what are some examples of amino acids that are hydrogen bond donors and acceptors?
- serine
- threonine
- glutamin asparagine
- histidine
- tyrosine
what are some examples of amino acids that are hydrogen bond donors?
- lysine
- arginine
- tryptophan
describe van der Waals interactions
less specific –> just hydrophobic interactions
due to distortions in electron clouds
why can we not determine affinity?
cannot determine van der Waals forces
describe dipole dipole interactions and their strength
due to permanent or induced dipoles from electronegativity –> can be induced
stronger than van der Waals but drug and target must be very close to each other!
what is an example of a part of a molecule with a permanent dipole?
ketone
describe pi-pi bonding
amino acid side chains with an aromatic ring interact with each other
due to 3 pairs of delocalized/unpaired electrons with transient delta positive charge interacting with transient delta negative charge
what are 4 amino acids that can undergo pi pi bonding?
- tryptophan
- phenylalanine
- histidine
- tyrosine
what is the water shell? how do we have drug-target interactions in the presence of the water shell?
water is everywhere –> at binding site, covering drug
must remove water for interaction to be stabilized –> this requires energy
when could a drug be ineffective in relation to the water shell?
if the energy required to remove the energy is greater than the stabilization energy, the drug may be ineffective
what is structured water?
water binds hydrophilic parts and forms strong H bonds at hydrophobic parts –> decreases entropy
how is structured water overcome? what does this result in?
when the hydrophobic region of a drug interacts with the hydrophobic region of the binding site, the structured water is overcome –> leads to increase in entropy and binding energy which is more favoured –> thermodynamic drive to have drug and target interact
how does water play a role in affinity?
once water shell is overcome –> water plays no role in affinity
how does adding polar groups to a drug affect its binding?
water solubility increases but must be solvent-accessible by having a part that protrudes from the binding site so water doesn’t have to be stripped away
how is affinity measured? what does this mean?
as Kd (in M)
concentration of drug required to bind 50% of receptors
small Kd = ____ affinity
small Kd = high affinity
what are the 3 units of M where drug affinity usually is?
- microM (10^-6)
- nanoM (10^-9)
- picoM (10^-12)
how does the equilibrium shift of [R]+[L]<=>[RL] when there are more intermolecular forces?
shift to the right
describe the core of an amino acid
ZWITTER ION at neutral pH –> ammonium ion and carboxylate ion –> separate positive and negative charged groups
what are some aliphatic amino acids? are they polar or nonpolar? where are these amino acids commonly found in cells?
- glycine
- alanine
- proline
- valine
- leucine
- isoleucine
- methionine
NONPOLAR –> all C and H
nonpolar so good for hydrophobic environment of membrane
what are some aromatic amino acids? which are polar, which are non-polar?
- phenylalanine (non-polar)
- tyrosine (polar)
- tryptophan (non-polar)
what is special about tryptophan?
super energy consuming to produce, so usually has specific important role
if just need a hydrophobic aromatic amino acid, use phenylalanine
what are some polar amino acids? what kind of interactions do they have?
- serine
- threonine
- aspargine
- cysteine
- glutamine
since they are polar –> they have dipoles and can have dipole-dipole interactions
what are some positively charged amino acids? what kind of interactions do they have? are they in transmembrane sequences?
- lysine
- arginine
- histidine
ionic interactions
usually not in transmembrane sequences - except lysine in EGF receptor HER2
what are some negatively charged amino acids?
- aspartate
- glutamate
describe a peptide bond
- how it is formed
- its electrons
- orientation
- H donor or acceptor?
- ribosome causes condensation reaction to cleave out water and join N-terminal with C-terminal
- electron rich –> electrons float around, resonance stabilized
- planar –> restricts mobility of protein to allow proper folding
- H donor AND acceptor
how is the 3D structure of protein stabilized?
intramolecular forces that make up secondary structures
why is the movement of things in water different from cytosol?
in cytosol, there are proteins and other things that have intermolecular forces that affect the movement
in secondary structures, what do ionic interactions produce?
salt bridge
why are DISULFIDE bridges important?
important for protein folding to make sure distant regions of a protein can interact
why can it be hard for drugs to cross the membrane?
many proteins in the membrane and other things to impede movement
what are 2 ways we can increase a drug’s effectiveness?
change its interactions so its easier to reach target
1. ex. more hydrophobic so its easier to get thru water in cytosol
2. ex. increased interaction in binding pocket to increase affinity and increase effect
