Problem set 4


Problem Set 4 Spring 2015 B541/C589

1)What are the three major classes of reversible inhibitors? Draw a kinetic scheme that shows which enzyme form these inhibitors target. How do these inhibitors affect basic enzyme kinetic constants (Km and kcat)? Why do they have these effects?

2)From a drug design perspective, what are the benefits and drawbacks of each kind of inhibitor?

3)What are the three basic classes of irreversible inhibitors? Outline how they might work, and give an example of each.

4) Explain how you would differentiate between an affinity reagent and a quiescent affinity inactivator.

What essential feature is different for these two classes?

5) THOUGHT PROBLEM. This is a toughie. Some classes of quiescent affinity reagents have extremely rapid first order inactivation rates (kinact). For extremely fast inactivations, it is often found that Ki goes up substantially. Why is this? What is the limit of kinact/Ki (hint, what are the units of this term?).

6) Explain how you would assay an irreversible inhibitor.

7) What conditions must be satisfied for something to be presumed a “mechanism-based inhibitor”?

8) Below are the structure of finasteride and testosterone. What reaction does finasteride inhibit?

What is its mechanism of action?

9) What are the two basic screening strategies used by pharmaceutical companies? What are the advantages and disadvantages of each?

10) What is the difference between a hit and a lead compound?

11) a)What are major barriers that must be overcome for a molecule to be orally bioavailable?

Please read the paper I have posted on orally administered ATP absorption. b) Why does ATP need to be enterically coated? How does one direct absorption of a molecule to the distal or proximal positions of the small intestine? Did ATP blood levels increase? How is this explained? Is it known whether ATP, AMP, or A is absorbed? c)Based on the results in this paper, how can you explain that manufacturers continue to produce sports supplements with added ATP?

12) Consider a screening process that screens one inhibitor at a time in a robotic process, versus one that screens a mixture of samples where each one contains 100 compounds. What are the benefits and disadvantages of these two different screening approaches?

13) What is the structural difference between morphine, heroin and codeine? Because of its structure, codeine is considered what kind of drug (as opposed to morphine)? What process is required for the activity of codeine to occur (outline it)? Explain the differences in activity between these molecules.

14) Why is the function of the liver so important for orally administered drugs? What is this process called? How does the liver typically modify molecules?