NANYANG TECHNOLOGICAL UNIVERSITY SEMESTER I EXAMINATION CBC922 Medicinal Chemistry. NOVEMBER TIME ALLOWED: 120 min

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1 AYAG TECLGICAL UIVERSITY SEMESTER I EXAMIATI CBC922 Medicinal Chemistry VEMBER TIME ALLWED 120 min ISTRUCTIS T CADIDATES 1. This examination paper contains TW (2) parts and comprises SIX (6) pages. 2. Answer all the questions. 3. Answer each question of PART A on the answer sheet provided and each question of PART B in the answer book. Answer each question of PART B beginning on a FRES page of the answer book. 4. This IS T an PE BK exam.

2 PART A Answer all multiple choice questions on the Answer Sheet, providing only one answer per question. 25 questions at 2 points each for a total of 50 points. 1. The fundamentals of Medicinal Chemistry involve A) synthetic chemistry and the design of new therapeutic agents B) an understanding and interaction with pharmacology C) the use of computational chemistry and molecular modelling D) all of the above 2. Which of the following types of compound is most likely to be a potent enzyme inhibitor A) a stable transition state analog B) a reactive substrate analog C) a stable product analog D) none of the above 3. Which statement is not correct about irreversible noncompetitive inhibitors? A) binds irreversibly to the binding site B) hydrogen bond is formed between the drug and the receptor C) messenger is blocked from the binding site D) increasing messenger concentration does not reverse inhibition 4. Which statement is not correct about type II diabetes? A) type II diabetes are insulin-dependent diabetes mellitus B) type II diabetes are non-insulin-dependent diabetes mellitus C) type II diabetes are adult-onset diabetes D) type II diabetes are more common than type I and III 5. Which of the following terms best describes a drug that binds to an active site and inhibits the enzyme, and where inhibition decreases when substrate concentration is increased? A) allosteric inhibitor B) non-competitive, irreversible inhibitor C) competitive, reversible inhibitor D) suicide substrate 6. What secondary messenger is generated as a result of the action of nitrous oxide (Viagra)? A) GTP B) ATP C) cyclic GMP D) cyclic AMP 7. Ion channel receptors A) are G-protein coupled B) are not G-protein coupled C) are much slower-acting than G-protein coupled receptors D) are tyrosine kinase coupled 2

3 8. G-Protein is composed of subunits. A) 3 α B) α, β, γ C) α, δ, ω, ε D) 2 α, γ 9. Which of the following statements is not true about receptors? A) most receptors are proteins situated in the cell membrane B) receptors contain a hollow or cleft on their surface which is known as a binding site C) receptors catalyse reactions on chemical messengers D) receptors bind chemical messengers such as neurotransmitters or hormones 10. Which of the following statements best describes pharmacodynamics? A) the study of how drugs reach their target in the body and how the levels of a drug in the blood are affected by absorption, distribution, metabolism and excretion B) the study of how drugs can be designed using molecular modelling based on a drug's pharmacophore C) the study of how a drug interacts with its target binding site at the molecular level D) the study of which functional groups are important in binding a drug to its target binding site, and the identification of a pharmacophore 11. Which of the following statements best describes pharmacokinetics? A) the study of how drugs reach their target in the body and how the levels of a drug in the blood are affected by absorption, distribution, metabolism and excretion B) the study of how drugs can be designed using molecular modelling based on drug's pharmacophore C) the study of how a drug interacts with its target binding site at the molecular level D) the study of which functional groups are important in binding a drug to its target binding site, and the identification of a pharmacophore 12. Which metabolites are likely to be formed (more than one is formed)? S S S - 2 S "metabolism" C 2 3 C 3 C drug metabolite 1 metabolite 2 metabolite 3 A) metabolites 1 and 3 B) metabolites 2 and 3 C) metabolites 1 and 2 D) all metabolites are likely (1, 2 and 3) 3

4 13. Drugs administered by the oral route of administration A) exhibit peak plasma concentrations at time zero B) the concentration of drug increases gradually reaching a maximum C) drug concentrations always fall below the therapeutic range D) onset of action always begins at time zero 14. The first pass effect can be defined as A) diffusion of drug through the BBB (Blood-Brain Barrier) B) the increased penetration of lipophilic drug through the biological membranes C) the loss of drug due to metabolism in the liver after absorption D) improved biological availability due to rapid distribution from the liver 15. The therapeutic range for a drug can be defined as A) peak and trough plasma concentration B) range of concentrations during which patient exhibits pharmacological effect C) range of concentrations during which patient exhibits toxicity D) none of the above 16. A lead compound is A) a drug on the market B) a receptor C) a pharmacophore D) a compound stimulating more research 17. The unlocking of the DA sequence of the human genome should enable future scientists to A) understand the molecular nature of cancer and therefore prevent or arrest it B) design new and specific acting medicines C) cure genetic diseases D) all of the above 18. QSAR is A) a synthetic method B) dependent upon crystal studies C) a modeling method D) an experimental method 19. The ansch Model A) is about the pharmacophore B) lists the properties to be used in a QSAR model C) is about the receptor D) is about the synthesis of a new drug 20. Molecular modification is A) requires significant structural information about the drug class and its receptor B) relies on biological screening, pharmacology and individual chemical syntheses to identify and optimize lead candidates C) is efficient because relatively few molecules are actually tested D) all of the above 4

5 21. Which of the following needs to be established before the search for a lead compound takes place? A) the pharmacophore B) structure activity relationships C) a bioassay D) patents 22. There are several sources and methods of discovering new compounds. Which of the following is most likely to lead to the discovery of a complex structure quite unlike any other previously discovered? A) combinatorial chemistry B) database mining C) screening plant extracts D) me too drugs 23. SAR shows that the important binding groups in morphine are the phenol, aromatic ring and amine. A diagram can be drawn which shows these functional groups and their relative orientations. What is the term for this? A) pharmacodynamics B) pharmacokinetics C) chromophore D) pharmacophore 24. Combinatorial chemistry can be useful at various stages of the drug design/development process. Which of the following is not such a stage? A) finding a lead compound B) optimising a lead compound C) structure determination of the lead compound D) structure-activity relationships of the lead compound 25. The drug development process includes the following phases A) preclinical testing B) phase I, II and III clinical testing. C) lead optimization D) A and B) are correct 5

6 PART B Answer each question beginning on a FRES page of the answer book. Question 1. Acetylcholine is the substrate for the enzyme acetylcholinesterase. 3 C Acetylcholine eostigmine a) Suggest what sort of binding interactions could be involved in holding acetylcholine to the active site. Acetylcholine contains an ester functional group and a quaternary nitrogen which is charged. Thus hydrogen bonds and ionic interactions may be important. There are also methyl groups which might fit into hydrophobic pockets. The actual binding interactions for acetylcholine are discussed in section (5 points=2+2+1) BA 3 C C BA 3 C C 3 C3 ionic b) eostigmine is an inhibitor of acetylcholinesterase. The enzyme attempts to catalize the same reaction on this inhibitor as it does with acetylcholine. owever, a stable intermediate is formed which prevents completion of the process and which results in a molecule being covalently linked to the active site. Identify the stable intermediate and explain why it is stable. Tell the type of this inhibition. (Serine is one of the key residues at active site) (3+2 point) The reaction catalysed by acetylcholinesterase on acetylcholine is the hydrolysis of the ester to produce acetic acid and choline. With neostigmine, the corresponding reaction would be the following Me 2 Me 3 Me 2 + Me 3 eostigmine In fact, this does not happen and a stable complex with the enzyme is formed. Following the mechanism through, serine acts as a nucleophile and a nucleophilic substitution reaction takes place on the urethane with loss of the phenol group. owever, once this has occurred, serine is 'capped' with a stable urethane group which is resistant to hydrolysis. 6

7 Stage 1 Stage 2 Me C Ar Me Ar Physostigmine Stage 3 -Ar Stage 4 Me C Ar Me C Ar + 2 ydrolysis VERY SLW Me Stable carbamoyl intermediate Full details of this process are described in section Question 2. Proflavine is a topical antibacterial agent which intercalates bacterial DA and was used to treat wounded soldiers during the second world war. What role (if any) is played by the tricyclic ring and the primary amino group? The drug can not be used systematically. Suggest why this is the case. (3+3+4 point) Proflavine contains a planar, heteroaromatic, tricyclic ring which could slip between the base pairs of DA and interact with the base pairs above and below it though van der Waals interactions. The amino groups are likely to be ionised at physiological p and could form ionic bonds with the charged phosphate groups of the DA sugar phosphate backbone (see also section ). The drug is unlikely to show any selectivity between the DA of bacteria and the DA of human cells. Therefore, it cannot be used systemically. 7

8 Question 3. Methylphenidate is used in the treatment of attention deficit hyperactivity disorder. Suggest possible metabolites based on the structure of this drug in the following. (3+3+ point) C 2 Me C 2 C 2 Me Question 4. List the key stages and phases of drug discovery and development. Briefly explain the main task in each of them. (1 points for each stage phase) Me C 2 Me C 2 Me C 2 Question 5. A pharmaceutical laboratory wishes to synthesize all the possible dipeptides containing the amino acids, tyrosine, lysine, phenylalanine, and leucine. Identify the number of possible dipeptides and explain how the lab would carry this out using combinatorial techniques. (3 points for 4x4=16; 7 points for cartoon picture) 4x4=16 End of Paper 8