Problems for Drug Design Courses (D) 1. State the general factors that need to be considered when designing a drug? 2. Define the meaning of the terms pharmacokinetic phase and pharmacodynamic phase in the context of drug action. List the main general factors that affect these phases 3. Describe, in general terms, how the technique of deconvolution can be used to identify the most active component in a combinatorial library consisting of groups of mixtures of compounds 4. Outline the technique of high-throughput screening 5.(a) How do biochemical assays differ from whole cell assays. What are the advantages of whole cell assays over biochemical assays (b)What is the significance of hit rates when assaying the results of an assay? (c) Suggest reasons for abnormally low and high hit rates in a high-throughput screen for a specific type of activity 6. The drug amphetamine(PhCH2 CH(NH2)CH;) binds to the protein albumin in the blood stream Predict how a reduction in pH would be expected to influence this binding? Albumin is negatively charged at pH 7. 4 and electrically neutral at pH 5.0 7. Suggest strategies for improving the stability of compound a in the gastrointestinal tract. What could be the general effect of these strategies on the pharmaceutical action of compound A? (A) 8. Use the Lipinski rules to determine which of the following compounds are likely to be orally bioavailable. Give a reason for your decision. (Note: The logP values are imaginary but should be taken as a real for this question only!) COOH HOOC HOOCProblems for Drug Design Courses (II) 1. State the general factors that need to be considered when designing a drug? 2. Define the meaning of the terms pharmacokinetic phase and pharmacodynamic phase in the context of drug action. List the main general factors that affect these phases. 3. Describe, in general terms, how the technique of deconvolution can be used to identify the most active component in a combinatorial library consisting of groups of mixtures of compounds. 4. Outline the technique of high-throughput screening 5. (a) How do biochemical assays differ from whole cell assays. What are the advantages of whole cell assays over biochemical assays. (b) What is the significance of hit rates when assaying the results of an assay? (c) Suggest reasons for abnormally low and high hit rates in a high-throughput screen for a specific type of activity 6. The drug amphetamine (PhCH2CH(NH2)CH3) binds to the protein albumin in the blood stream. Predict how a reduction in pH would be expected to influence this binding? Albumin is negatively charged at pH 7.4 and electrically neutral at pH 5.0. 7. Suggest strategies for improving the stability of compound A in the gastrointestinal tract. What could be the general effect of these strategies on the pharmaceutical action of compound A ? O HO HO O (A) 8. Use the Lipinski rules to determine which of the following compounds are likely to be orally bioavailable. Give a reason for your decision. (Note: The logP values are imaginary but should be taken as a real for this question only!) N H N OH COOH N N N O N N OH OH HO HOOC H2N CH3 NH2 N O OH HOOC H2N CH3 NH2 LogP=5.2 LogP=2.6 LogP=5.7