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 HOOC
Problems 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
9. What is the significance structure of a drug as far as drug design is concerned? 10. Outline why the stereochemistry of a compound is important in drug design 11. Outline by means of suitable examples what the significance of (a) structurally rigid groups, (b) conformations and(c)configuration has on the design of new drugs 12. Why is water solubility an important factor in the action of drugs? 13. Define the meaning of the terms: (a)ideal solution and(b) polar solute 14. List the structural features that would indicate whether a compound is likely to be reasonably ater soluble Illustrate the answer by reference to suitable examples 15. Outline three general methods by which the water solubility of a compound could be improved without affecting its type of biological action 16. Suggest, by means of chemical equations, one route for the introduction of each of the following residues into the structure of 4-hydroxybenzenesulphonamide (a) an acid residue (b)a basic residue (c)a neutral polyhydroxy residue 17. State the full wording of the abbreviation"SAR" Describe the general way in which SAr is ed to develop a drug 18.(a) Explain why chloride and fluorine are normally the preferred halogen substituents for a SAR Investigation (b) What alternative halogen containing group could be used in place of chlorine? Give one reason for the use of this group 19. Explain the meaning of the terms:(a) bioisostere and(b) pharmacophore 20. Suggest how the introduction of each of the following groups into the structure of a lead could be expected to affect the pharmacokinetics of the resultant analogue:(a) a sulphonic acid group, (b) a methyl group and (c)a thiol group. Assume that these groups are introduced into the section of the lead, structure that does not contain its pharmacophore
9. What is the significance structure of a drug as far as drug design is concerned? 10. Outline why the stereochemistry of a compound is important in drug design. 11. Outline by means of suitable examples what the significance of (a) structurally rigid groups, (b) conformations and (c) configuration has on the design of new drugs. 12. Why is water solubility an important factor in the action of drugs? 13. Define the meaning of the terms: (a) ideal solution and (b) polar solute 14. List the structural features that would indicate whether a compound is likely to be reasonably water soluble. Illustrate the answer by reference to suitable examples. 15. Outline three general methods by which the water solubility of a compound could be improved without affecting its type of biological action. 16. Suggest, by means of chemical equations, one route for the introduction of each of the following residues into the structure of 4-hydroxybenzenesulphonamide. (a) an acid residue (b) a basic residue (c) a neutral polyhydroxy residue. 17. State the full wording of the abbreviation “SAR”. Describe the general way in which SAR is used to develop a drug. 18. (a) Explain why chloride and fluorine are normally the preferred halogen substituents for a SAR investigation. (b) What alternative halogen containing group could be used in place of chlorine? Give one reason for the use of this group. 19. Explain the meaning of the terms: (a) bioisostere and (b) pharmacophore. 20. Suggest how the introduction of each of the following groups into the structure of a lead could be expected to affect the pharmacokinetics of the resultant analogue: (a) a sulphonic acid group, (b) a methyl group and (c) a thiol group. Assume that these groups are introduced into the section of the lead, structure that does not contain its pharmacophore
21. Outline the fundamental principle underlying the Qsar approache to drug design 22. Lipophilicity, shape and electron distribution all have major influence on drug activity. State the parameters that are common used as a measure of these properties in the QSar approach to drug design. 23. What are the advantages and disadvantages of using molecular mechanics to model molecular structures 24. Explain the significance of the terms global and local minimum energy conformations 25 Describe, in outline only, what is meant by(a) molecular dynamics and(b) docking 26)(a)What is the principle that forms the basis of the quantum mechanical approach to molecular modeling? (b) State and name the equation that is the starting point of the wave mechanical approach to molecular modeling 27 Explain the meaning of the term pharmacophore 28. Explain why a molecular with a flexible structure would be more likely to be more active than its analogue with a rigid structure. The compound a and b both bind to the same target site, which of them would you expect to be the most active? State the basis of your decision NH2 H3C NH2
21. Outline the fundamental principle underlying the QSAR approache to drug design. 22. Lipophilicity, shape and electron distribution all have major influence on drug activity. State the parameters that are common used as a measure of these properties in the QSAR approach to drug design. 23. What are the advantages and disadvantages of using molecular mechanics to model molecular structures. 24. Explain the significance of the terms global and local minimum energy conformations. 25. Describe, in outline only, what is meant by (a) molecular dynamics and (b) docking 26) (a) What is the principle that forms the basis of the quantum mechanical approach to molecular modeling? (b) State and name the equation that is the starting point of the wave mechanical approach to molecular modeling. 27 Explain the meaning of the term pharmacophore. 28. Explain why a molecular with a flexible structure would be more likely to be more active than its analogue with a rigid structure. The compound A and B both bind to the same target site, which of them would you expect to be the most active? State the basis of your decision. H3C NH2 H3C NH2 (A) (B)