Chem 455 Exam 2 Flashcards
receptors
GPCRs, ion channels, nuclear receptors, receptor tyrosine kinases
they are often integral proteins in membranes and are chiral
what are 2 fundamental characteristics of a receptor
recognition capacity and amplification
recognition capacity
binding of molecules
amplification
initiation of biological response
Kd
measures the affinity to receptor aka is a dissociation constant and roughly represents the concentration of the drug that gives 50% drug receptor complex
(drug)(receptor)/(complex)
Forces involved in drug receptor complex
molecular surfaces must be complementary
forces are usually weak and reversible
decreases in G of -5.45 kcal/mole changes binding eq from 1% to 99%
ionic interactions
G = -5kcal/mol
Basic groups = His, Lys, Arg (cationic)
Acidic groups - Asp, Glu (anionic)
ion-dipole, dipole dipole interactions
have charge transfer complexes
- Donor group contains pi-electrons/nonbonded electrons
- Acceptor groups have electron deficient pi-orbitals
hydrogen bonding
G= -3 to -5 kcal/mol
interaction between X-H (x is electronegative) and N O or F
Hydrophobic interaction
G = -.7kcal/mole per CH2-CH2
Increase in entropy of H2O decreases free energy and stabilizes it
Binding of one methyl group in hydrophobic pocket can improve binding by -1.5kcal/mole (factor of ~12) “magic methyl”
Pi-pi interactions between aryl groups
Cation pi interaction
G = -.5 to -7lcal/mol
Most common is Trp but Phe, Tyr, His
Halogen Bonding
G = -1 to -15kcal/mol
Covalently bonded I>B>Cl»F electron acceptors for electron rich O, N, S
Results from sigma-hole - positively charged region on the back side of the halogen along the R-X bond axis
van der waals interactions
G = -.5kcl/mole per CH2/CH2
As molecules approach, temporary dipoles in one atom induce opposite dipoles in another
Cooperativity w/ several interactions
Lots of weak add up to strong (once first interaction occurs, translational entropy is lost, lowering entropy loss in next)
agonist
produce the same biological response as natural enzyme or ligand and show structural similarity to them
displays positive efficacy
Antagonist
blocks response of particular enzyme/ligand and can show little structural similarity to natural ligand; noncompetitive and competitive binding sites
displays 0 efficacy
Partial agonist
does not produce 100% of biological response as natural enzyme/ligand
displays positive efficacy
Inverse agonist
produces opposite effect of natural ligand/enzyme
displays negative efficacy
affinity
complexation with receptor
efficacy
measure of maximum biological effect that drug can produce as a result of receptor binding; initiation of response
Three point attachment theory
enantiomers cannot be distinguished by receptor by 2 binding sites- needs at least 3 sites
atropisomerism
occurs when there is hindered rotation about a single bond as a result of steric or electron constraints causing slow interconversion of two conformers
Eutomer
more potent enantiomer
Distomer
less potent enantiomer
Three point attachment theory
Enantiomers cannot be distinguished by two binding sites, receptors need at least three sites
Advantages of enzymes
they can be purified more easily since they are cytosolic and membrane binding is not an issue
enzyme inhibitors can be designed from natural substrates
mechanism of enzyme can be used in design of transition state analog inhibitors
