Problem 1
What are some of the advantages and disadvantages of random screening?
Problem 2
Name some situations in which the endogenous ligand of a new biological target may not serve as a good lead compound.
Problem 3
Cholecystokinin C-terminal tetrapeptide (CCK-4) is the smallest (molecular weight 596.7, CLog \(P=-2.1\) ) active form of CCK found in the brain. Release of CCK in the brain is believed to promote anxiety. (a) What would be possible concerns with using CCK-4 as a lead compound for an orally active antianxiety drug? (b) Name some alternative approaches to identifying a lead compound.
Problem 4
Consider the earlier days, when drug screening was often done in whole animals, vs. today's more modern methods of drug discovery that often start with a highthroughput screening assay. Which of the following factors do you think are most influential in driving the change toward modern methods? a. Amount of compound needed for the first test. b. Expense of animals needed for the first test. c. Early information on in vivo pharmacokinetic properties. d. Ability to have a direct indication of pharmacodynamic properties.
Problem 6
"Semisynthesis" is a term used to describe preparation of analogs of a natural product using the natural product isolated from natural sources as the starting material. What are some likely pros and cons of the semisynthesis approach?
Problem 9
A new protein was identified that appears to be abundant in individuals prone to a certain type of cancer. You are trying to identify a molecule that will bind to this protein as a lead compound, but you do not know the structure or function of the protein. How would you proceed?
Problem 10
The \(\mathrm{LD}_{50}\) for a potential antiobesity compound was found to be \(10 \mathrm{mg} / \mathrm{kg}\) and the \(\mathrm{ED}_{50}\) was \(2 \mathrm{mg} / \mathrm{kg}\). Is this an important drug candidate? Why or why not?
Problem 12
What are some potential problems in using bioisosteric replacements for lead modification?
Problem 13
a. A claimed advantage of solid-phase chemistry was that because excess reagents could be used and then readily removed (by filtration), purer products should result. What is the fallacy in this argument? b. Running many reactions in parallel generally implies that they are all done in the same solvent, at the same temperature, for the same time period, and with the same method of agitation, and that they are worked up in the same way. The efficiency advantages in this approach are evident. Name at least one potential disadvantage. c. Combinatorial power is increased substantially when more points of diversity are used in a library, i.e., many more compounds can be made using a comparatively small number of monomers. Give two reasons why more compounds under this circumstance may not be an advantage.
Problem 14
In solid-phase chemistry, the starting material and product of a reaction are bound to a solid support and the reagents are in solution. In solution-phase chemistry, the starting material and product are in solution and either reagents or reactant scavengers are frequently bound to solid support. What are some advantages of the latter mode of operation?
