Lecture 4 Flashcards
Drug selectivity
Bind selectivity of a drug – higher affinity for ligand/protein over another or affinity for one receptor over another
how well a drug has therapeutic effect w/o sides
NSAIDs
targets COX and blocks prostaglandin production. high selectivity to inhibit COX. non specific inhibition can lead to G1 binding
COX 1
don’t want to inhibit, responsible for bodily regulations
COX 2
responsible for inflammatory response, so we want to inhibit this
designed to avoid G1 sides – celecoxib and rofecoxib, 60% of COX1 and COX 2 are identical
COX2 has valine which has less steric hinderance than isoleucine in COX 1
Targeting allosteric site for therapeutic use
goal is to target allosteric site not catalytic site due to higher selectivity at allosteric site since there is better control with increasing or decreasing activity.
example: PTP4A3 is overexpressed in many human cancer and JMS designed to be allosteric
Enzyme inhibition and activiation
coopertivity and effectors
bind non covalently to a site distinct from active site — not chemically modified during reaction
most often multiple subunits, identical or non identical – effector binding leads to conformation change that propgates to other subunits
heterotrophic
ligand in effector site not the same as substrate ligand
homotrophic
same ligand as substrate
sigmoidal curve
shows coopertivity, whereas hyperbolic curve shows noncoopertivity
higher steepness/slope means more cooperative
regulation enzyme
GOUT: inflammatory disease caused by overproduction of uric acid
hyperuricemia: caused by overproduction of purine nucleotides caused by abnormal enzyme activity.
PRPP synthases catalyze rate lmiting step and excessive PRPP can lead to uric acid overproduce
PT study: increased PRPP in RBCs consistent with dysfunctional PRPP synthetases
ADP binds at allosteric sites, so PRPP normally inhibited by ADP
