Medicinal Chemistry

GENERAL OBJECTIVES:

1. Understand some of the historical background to the discovery and use of drugs

2. Understand basic concepts in the study of drugs and medicines

3. Understand drug action at enzymes

4. Understand drug action at receptors

5. Understand drug action at nuceic acids (DNA and RNA)

6. Understand drug discovery and development

7. Understand pharmacokinetics

8. Describe opium analgesics and their interaction with opiate receptors

9. Describe the discovery and development of transition state inhibitors of HIV-1 protease

Students should be able to:

1. describe, briefly, the history of opium and its use in medicine

2. describe the isolation and initial medical uses of morphine

3. discuss the elucidation of the structure of morphine

4. understand the simple lock and key mechanism for morphine binding to receptors on the surface of nerve cells

5. discuss the structures and properties of 6-acetyl morphine, 3,6-diacetyl morphine, codeine and dihydrocodeine

6. know the history of some antibacterial agents

7. know that bacteria were first identified by van Leeuwenhoek, associated with disease by Pasteur and Lister and confirmed by Koch

8. understand that Ehrlich initiated chemotherapy

9. describe the discovery of Salvarsan, proflavine and prontosil

10. describe the history of penicillin

11. Know the parts played by Flemming, Florey, Chain and Hodgkins.

12. draw the structure of penicillin

13. explain the lability of penicillin

14. use curly arrows to draw the mechanism of the base promoted hydrolysis of penicillin

15. use curly arrows to draw the mechanism of the acid catalysed hydrolysis of penicillin

16. know that penicillin inhibits an enzyme involved in constructing the cell wall of bacteria

1. Understand that drugs may be classified (a) by their phamocological effect, (b) by their chemical structure, (c) by their intended target or (c) by their site of action

2. Know basic cell structure

3. know that drugs produce their effects by interacting with proteins (receptors, enzymes, etc) nucleic acids (DNA) lipids (cell membranes) and structural carbohydrates.

4. Understand (revise) the structure of proteins and discuss the interaction of drugs with receptor binding sites.

5. Describe receptor recognition and binding of drugs in terms of: specificity, complementarity of shape, complementarity of electronic nature and the types of binding forces available

6. Explain stereospecificity in drug-receptor binding

1. Understand (revise) chemical catalysts and catalysis

2. Understand (revise) enzymes as catalysts

3. Understand (revise) enzyme kinetics

4. Describe substrate binding by enzymes

5. describe molecular mechanism of catalysis for an enzyme

6. discuss competitive inhibitors

7. discuss non-competitive (irreversible) inhibitors

8. understand non-competitive, reversible (allosteric) inhibitors

9. discuss the catalytic role of enzymes in terms of substrate binding, molecular mechanisms of catalysis (general acid/base, nucleophilic groups, transition state stabilisation)

10. Give examples of enzyme inhibitors as antibacterial drugs

11. Give examples of enzyme inhibitors as antiviral drugs

12. Give examples of enzyme inhibitors against the body's own enzymes

1. Students should be able to: understand what receptors are and what they do

2. describe some neurotransmitters and hormones

3. know that receptor binding induces conformational change which brings about a biological effect

4. describe ion channels and their control

5. describe the activation of membrane bound enzymes describe how a receptor may change its shape upon binding its ligand

6. discuss the design of agonists as drugs

7. describe the binding of agonists in terms of structure, shape and electronic nature

8. discuss the design of antagonists

9. describe antagonists acting at the binding site

10. describe antagonists acting outwith the binding site

11. discuss partial agonists and inverse agonists

12. describe desensitisation and sensitisation

13. discuss tolerance and dependence

14. know that there are cytoplasmic receptors

15. understand receptor types and subtypes

1. Understand (revise) the primary secondary and tertiary structure of DNA

2. describe the action of intercalating agents

3. describe the action of alkylating agents

4. draw the structures of: nitrogen mustard and outline its cross-linking of DNA

5. draw the structure of cisplatin and outline its cross linking of DNA strands

6. describe the action of "cutting" agents

7. understand the structures of t-RNA, m-RNA and r-RNA

8. describe the action of drugs on RNA

9. discuss drugs related to nucleic acid building blocks

10. draw the structures of acyclovir and AZT and briefly describe their mechanisms of action

1. Discuss the screening of natural products to find new drugs

2. describe the exploitation of medical folklore

3. describe the screening of synthetic "banks" of compounds

4. discuss starting from a known ligand such as a hormone

5. discuss the role of serendipity and the prepared mind

6. understand the saying that "drugs are discovered in the clinic"

7. discuss structure-activity relationships and the binding role of: hydroxyl groups, amino groups, aromatic rings, double bonds, carbonyl groups, and amides

8. define isosteres and give examples

9. discuss drug design to: increase activity, reduce sideeffects, improve pharmacokinetics (absorption, metabolism and excretion), improve synthesis and factory
production

10. discuss the variation of substituents in drug development

11. discuss chain extensions and contractions

12. discuss ring expansions and contractions

13. discuss isosteric replacements, discuss rigidification of the structure

1. Outline how drug uptake, distribution, metabolism and excretion affect the ability of a drug to reach its target

2. discuss the design of drugs to influence their: chemical stability and metabolic stability

3. discuss drug design to optimise distribution by changing the balance of: hydrophobicity, hydrophilicity, charge, polarity

4. discuss the design of drugs to confer resistance to chemical hydrolysis and metabolic transformations

5. describe some methods of targeting drugs to their ste of action

6. describe some examples of prodrugs and how they work

7. discuss common methods of administration of drugs

8. discuss the formulation of drugs

1. Describe the development of narcotic analgesics as an example of traditional medicinal chemistry

2. describe the isolation of morphine

3. discuss the structure and properties of morphine

4. discuss structure-activity relationships of morphine

5. discuss variation of substituents

6. discuss simplification and dissection

7. describe rigidification

8. discuss extension of the molecule

9. Discuss receptor theories of the opium analgesics (Beckett-Casy Hypothesis and multiple receptor theories)

10. describe agonists and antagonists

11. describe the discovery of enkephalins and endorphins.

1. Understand (revise) the mechanism of pepsin catalysed hydrolysis of peptide bonds.

2. Understand (revise) the mechanism of pepstatin inhibition of the catalysed hydrolysis

4. Describe the extensions of these results to the design and investigation of transition state analogue inhibitors for other aspartyl proteases such as Renin

5. Describe the appearance of a new disease, AIDS, in the late 1970 - early 1980s

6. Describe the discovery of the HIV virus in Paris by Luc Montagnier in 1983

7. Describe the discovery of the enzyme HIV-1 protease, its function and mechanism of action describe the design of transition state analogue inhibitors for HIV-1, their structures, mechanism of action, advantages and disadvantages

8. describe the development of improved analogues leading up to the drugs used in the clinic such as: Saquinavir, ritonavir, Indinavir, nelfinavir and Amprenavir.