PHRM 824: Lecture 5 Flashcards
drugs often bind to their targets at ____ concentrations
low
what is a pharmacophore?
core part of a drug molecule that is interacting with the receptor active site and induce a biological response
4 types of binding forces
1) covalent bond
2) electrostatics
3) hydrophobic interactions
4) aromatic ring interactions
drugs of this type involve irreversible target modification and thus biological actions of long duration
covalent bond
energy for covalent bond is
50 to 150 kcal/mol
energy used for this is considered to be high
covalent bond
covalent bonds are generally ______ rather than ______
electrophilic
nucleophilic
electrostatic interactions involve?
1) ion-ion or charge-charge interactions
2) ion-dipole
3) dipole-dipole
these are very strong attractive forces, operate over long distances
ion-ion or charge-charge interaction
what is the kcal/mol for ion-ion or charge-charge interactions?
5-10 kcal/mol
this is a charged species like solvation
ion-dipole
hydrogen bond is considered in which of the 4 groups
electrostatics
this is a particularly strong dipole-dipole interaction between a hydrogen atom and an electronegative atom (O,N,F)
hydrogen bond
are hydrogen bonds stronger than ion-ion, ion-dipole, or dipole-dipole interactions?
not as strong
about 1/10th as strong
this is an interaction between non-polar regions of drug and receptor
hydrophobic interactions
this is a type of hydrophobic interactions
van der waals forces
the energy of van der waals forces is what
0.5-1 kcal/mol
in van der waals reactions, they don’t involve _____ per se; rather their driving force is an ____ in _____ resulting from the release of ___ ___ molecules initially bound to the ____ ____ surfaces
- bonds
- increase, entropy
- water molecules
- non-polar
this type of binding includes a charge transfer
aromatic ring interactions
in aromatic ring interactions wham charat happens in a charge transfer?
- two aromatic rings interact cloesely, resulting in a small electron ‘flow’ between them
aromatic ring interactions: typically occurs between ___ ___ and ___ ___ aromatic rigns
- electron-rich
- electron-deficient
aromatic rings can often interact favorably when they are put close together. You can get some degree of electron sharing between the ____ electrons. We call this?
- pi
- pi stacking
in aromatic ring interactions instead of dipole moments they have?
quadripole moments
aromatic ring interactions have two types
1) charge transfer
2) cation-pi
aromatic ring interactions: cation-pi
a lot of cations bind to the receptor or enzyme by being sequestered around ___ ____ ____ ____
- aromatic rich amino acids
aromatic ring interactions: cation-pi
some of these positively charged amines can be?
surrounded on almost all sided by 4 aromatic groups to stabilize that
in this reaction, the electron rich pi system cloud neutralizes the charge of the cation - primarily electrostatic
aromatic ring interactions: Cation-pi
and example of this cation- pi is?
acetylcholine binding to tryptophan
what drug receptor example did we use?
beta-2-adrenergic receptor and isoproterenol
every drug uses more than 1 way to bind to its target TRUE or FALSE
TRUE
when we think of steric properties we think of
steric clash
steric effects can arise from the presence of ____ groups on a drug molecule
bulky
steric properties: often works that you want to _____ the ______ and usually represented by ____ effects of releasing ___ that might be taking up space
- fill the pocket
- tropic
- water
most drugs interact with their protein targets
non-covalently
this is the rate constant for association of the complex
ka
this is the rate constant for dissociation of the complex
kd
the equilibrium ____ _____ ( ) is generally considered synonymous with the term affinity
- association constant, ka
the higher the ka value?
the more favorable - higher affinity binding
the smaller the kd?
the more tightly it is bound = increased affinity and less likely to dissociate
binding energies typically range from ______ kcal/mol
6-15
free energy values are _____ if the association between drug and receptor is favorable AKA ta
- negative
- Ka > Kd
the more negative the delta G the?
great the affinity
indirect steric effects: a molecule with a 2D structure similar to that of an active drug may be inactive if it cannot?
adopt the necessary conformation to activate the target receptor
indirect steric effects: if a molecule cannot adopt the necessary conformation to activate the target receptor it binds to an
inactive receptor state
what happens really in indirect steric effects?
the molecule may be unable to adopt a key conformation because it has bulky groups that prevent rotation about one of its bonds
this is the concentration of drug that gives half maximal activity
EC50
what is an example of us looking at EC50?
- kill cancer, so effective concentration of durg at which you killed 1/2 of your cancer cells
concentration of drug that vies half-maximal receptor binding
Kd
basically Kd is telling us
receptor is 1/2 drug bound
