- Enzyme has catalytic active site where reaction occurs - Receptor has ligand binding site

1. Drug-Target Interactions Flashcards by Zara Jalil

what is a target?

any cellular macromolecule that a drug binds to –> enzyme, receptor, protein, or DNA

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what is a drug?

chemical substance that interacts with target to produce beneficial physiological effect

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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

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what is the difference between a drug and chemical?

both bind at target but drug produces biologically beneficial effect

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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)

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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

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ENZYMES vs RECEPTOR

Enzyme has catalytic active site where reaction occurs
Receptor has ligand binding site

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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

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describe the lock and key

less accurate now –> perfect match between drug and target

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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

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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

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what is affinity?

measure of the TIGHTNESS with which a drug binds to the receptor

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what does affinity depend on?

quality and number of intermolecular forces

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besides affinity, what 2 other factors influence binding?

water shell
pH

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describe covalent bonds and their energy

no affinity involved –> they are 1 molecule, there is no dissociation constant

highest energy!

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describe ionic interactions and their length

not very specific –> just cation-anion attraction

pretty long bonds

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what is an example of ionic interaction?

C-terminus binding N-terminus

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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

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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

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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

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what are some examples of hydrogen bond acceptor?

C=O, C=N-C, C-O-C

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what is an example of hydrogen bond donor?

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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?

1. tryptophan 2. phenylalanine 3. histidine 4. 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