IMC 06 and 08: Fundamentals of Drug-target Interactions Flashcards
What are the the typical features of drug binding sites?
hydrophobic, deep cavity that is accessible to the protein surface
What are the 5 types of drugs?
- substrate analogues
- transition state analogies
- allosteric modulators
- targeted covalent inhibitors
- prodrugs
What are substrate analogues?
structurally mimic the naturally occurring binding partner (which could be enzyme substrate, cofactor, metabolite, or signaling molecule)
What are transition state analogues?
drug substance that mimics the transition state of an enzymatic reaction
What are allosteric modulators?
drug molecules that bind to a regulatory site of the protein, and not at the substrate/ligand binding site
What are targeted covalent inhibitors?
drug molecules that possess a chemically reactive group that will interact with a target protein to make an irreversible covalent bond
What are prodrugs?
drug substances that are metabolized in the body to produce the active form of the drug
Describe properties of drug metabolites (metabolized drugs).
- more polar
- less membrane permeable
- easier to excrete
What is phase I of metabolism?
modification
- oxidation, reduction, and hydrolysis of functional groups
What is phase II of metabolism?
conjugation
- attaching functional groups to make charged species (ie. glycine, glutathione, or glucuronic acid)
What is phase III of metabolism?
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
What are the 6 non-covalent interactions in which drugs interact with their targets?
- ionic interactions
- hydrogen bonding
- van der Waals forces – dipole-dipole, ion- or dipole-induced dipole, London dispersion
- hydrophobic interactions
- pi stacking
- cation-pi interactions
What are ionic interactions?
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)
What is hydrogen bonding?
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
van der Waals
What are dipole-dipole interactions?
interactions between δ+ and δ-
van der Waals
What are ion-induced dipoles or dipole-induced dipoles?
ions or partial charges will induce dipoles by attracting or repelling electrons in the electron cloud
van der Waals
What are London dispersion forces?
temporary dipole-induced dipole
- weakest
- because electron density is probabilistic, partial charges may result from random electron movement which can induce dipoles as well
What are hydrophobic interactions?
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
What is pi-stacking?
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
What are cation-pi interactions?
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
