Lecture 3

Question 1

Antibiotic as TS analogue

Answer 1

compound that closely resembles the transition state should bind tightly to the enzyme and be effective therapeutic
active site of enzyme is formed to perform a certain chemical reaction

Question 2

Ex - TS analogue

Answer 2

helicobacter targets MTAN – essential for bacteria that we dont have MTAN is dissociative TS

Question 3

Irreversible Inhibitor

Answer 3

compounds that chemically modify and inactivate the enzyme
mimic natural substrate and bind to active site to utilize binding specificity of target enzyme for selectivity
react w/ active site surface residues

Question 4

Irreversible inhibitor ex- dihydrofolate reductase

Answer 4

aspirin: inhibition of cyclooxygenase (COX) they bind channel for substrate access to active site and prevents access to active site

Question 5

Mechanism based Irreversible inhibitor

Answer 5

uses catalytic properties of active site to generate a chemically active species – innocuous reversible is converted to an irreversible inhibitor
avoids sides of highly reactive chemical compounds
suicide inhibitors, trojan horse inhibitors

Question 6

Mechanism based Irreversible inhibitor ex

Answer 6

Myeloperoxidase (MPO) heme containing enzyme produced in nuetrophils that functions to kill microorganisms w/ H2O2 for oxidative damage

Question 7

Covalent inhibitor

Answer 7

crystal structure of MPO after inactivation by TX2 – TX 2 covalntly attached to heme via thioester bond – heme binds O2 for redox
acetylcholine esterase is targeted by sarin that disables enzyme for hours/days
can be displaced by pralidoxine: poison very stable that wont break down

Question 8

HIV protease

Answer 8

HIV infects humans & causes AIDS w/o treatment can result in infection, cancer, death
HIV rna genome encodes for long polypeptide chain GAG. HIV binds are an immature viron w/ GAG in tract and GAG cleared into 3 proteins by protease

Question 9

HIV inhibitor

Answer 9

goal is to create compound that binds HIV protease active site w/ high affinity and dont allow mutation of protease that would lower the affinity for drug that causes resistance
Ex. DRV is potent therapy for treatment-naive patients & patients w/ HIV resistant to other antivirals

Question 10

HMG-COA

Answer 10

HMG-CoA reductase catalyzes deacylation to form mevalonate and CoA which is at rate limiting step of cholesterol
mevalonate is precursor to cholesterol and commitment step
statins compete with HMG-CoA that binds to mevalonate moiety of HMG-CoA