IMC 06 and 08: Fundamentals of Drug-target Interactions

Question 1

What are the the typical features of drug binding sites?

Answer 1

hydrophobic, deep cavity that is accessible to the protein surface

Question 2

What are the 5 types of drugs?

Answer 2

• substrate analogues
• transition state analogies
• allosteric modulators
• targeted covalent inhibitors
• prodrugs

Question 3

What are substrate analogues?

Answer 3

structurally mimic the naturally occurring binding partner (which could be enzyme substrate, cofactor, metabolite, or signaling molecule)

Question 4

What are transition state analogues?

Answer 4

drug substance that mimics the transition state of an enzymatic reaction

Question 5

What are allosteric modulators?

Answer 5

drug molecules that bind to a regulatory site of the protein, and not at the substrate/ligand binding site

Question 6

What are targeted covalent inhibitors?

Answer 6

drug molecules that possess a chemically reactive group that will interact with a target protein to make an irreversible covalent bond

Question 7

What are prodrugs?

Answer 7

drug substances that are metabolized in the body to produce the active form of the drug

Question 8

Describe properties of drug metabolites (metabolized drugs).

Answer 8

• more polar
• less membrane permeable
• easier to excrete

Question 9

What is phase I of metabolism?

Answer 9

modification

• oxidation, reduction, and hydrolysis of functional groups

Question 10

What is phase II of metabolism?

Answer 10

conjugation

• attaching functional groups to make charged species (ie. glycine, glutathione, or glucuronic acid)

Question 11

What is phase III of metabolism?

Answer 11

further modification and excretion – modification of conjugated groups in phase II

• note: many drugs will be excreted after phase II metabolism – phase III is only sometimes invoked

Question 12

What are the 6 non-covalent interactions in which drugs interact with their targets?

Answer 12

• ionic interactions
• hydrogen bonding
• van der Waals forces – dipole-dipole, ion- or dipole-induced dipole, London dispersion
• hydrophobic interactions
• pi stacking
• cation-pi interactions

Question 13

What are ionic interactions?

Answer 13

positive and negative charges attract

• balancing positive and negative charges reduces overall energy
• especially important in hydrophobic environments (active sites and hydrophobic protein core)
• on the protein surface, ions interact with water molecules (ion-dipole interactions which are stabilizing)

Question 14

What is hydrogen bonding?

Answer 14

interaction between heteroatom (usually oxygen or nitrogen) and hydrogen atom attached to another heteroatom

• subtype of dipole-dipole interactions
• differences in electronegativity make hydrogen atoms δ+ and heteroatoms δ- (N and C)
• partially positive (δ+) hydrogen atoms will interact with lone pairs on N and O to make hydrogen bonds
• hydrogen bond donor (HBD) has δ+ hydrogen atom
• hydrogen bond acceptor (HBA) is δ- and has lone pair in hybrid orbital – ie. not involved in an aromatic pi system

Question 15

van der Waals

What are dipole-dipole interactions?

Answer 15

interactions between δ+ and δ-

Question 16

van der Waals

What are ion-induced dipoles or dipole-induced dipoles?

Answer 16

ions or partial charges will induce dipoles by attracting or repelling electrons in the electron cloud

Question 17

van der Waals

What are London dispersion forces?

Answer 17

temporary dipole-induced dipole

• weakest
• because electron density is probabilistic, partial charges may result from random electron movement which can induce dipoles as well

Question 18

What are hydrophobic interactions?

Answer 18

describes favourable interactions between two hydrophobic groups in an aqueous environment

• interaction of hydrophobic groups reduces the exposed hydrophobic surface area, thereby reducing the area of highly ordered network of water molecules
• entropic effect – increasing disorder is favourable
• major driving force for protein folding and for drug binding to protein active sites

Question 19

What is pi-stacking?

Answer 19

delocalized pi system increases electron density above and below the aromatic ring

• carbon atoms in the ring are therefore δ+
• weaker than van der Waals forces – small role in protein folding
• control substrate and drug binding properties

Question 20

What are cation-pi interactions?

Answer 20

cations (+) can interact with the delocalized electron (-) cloud a benzene ring

• common in proteins, tend to be strong, but depend on cation and aromatic system