Natural Products In Drug Discovery

Question 1

What are the 5 key requirements of an orally administered drug?

Answer 1

i) must survive exposure to stomach acids and digestive enzymes
ii) must be absorbed from the gut into the blood supply
iii) must survive passage through the liver -( contains large numbers of metabolic enzymes
iv) must be effectively distributed around the body without being competitively absorbed by fat tissue
v) has to have a reasonable life time inside the body and not be rapidly excreted

Question 2

What happens if the drug is too hydrophilic?

Answer 2

It will be unable to pass rough the cell membrane of the gut wall because the lipid bilayer is hydrophobic

Question 3

What happens if the drug is too lipophilic?

Answer 3

It will be insufficiently water soluble to gain good contact with the gut wall

Question 4

What is Lipsinki’s rule of 5?

Answer 4

1) the drug candidate must have a molecular weight of

Question 5

What is the process of a lead discovery?

Answer 5

• selection on an appropriate drug target for a given disease state
• development of a bioassay - should ideally be simple, rapid and carried out on intact cells (in vitro)
• discovery of a lead compound wi the desired effect on the drug target

Question 6

What is the final part of the lead discovery process?

Answer 6

Discovery of a lead compound which possesses the desired pharmacological activity and which represents starting point of subsequent drug design and development

Question 7

What are two sources of potential lead compounds?

Answer 7

• structural alteration of the natural substrate or ligand

- natural enzyme or ligand substrate for a receptor

Question 8

Give an example of where a natural substrate for an enzyme or ligand for a receptor has been used as a lead compound for drug discovery.

Answer 8

-adrenaline and noradrenaline used to develop salbutamol (asthma) and dobutamine (heart failure)

Question 9

What effects do adrenaline and noradrenaline have on the body?

Answer 9

• both are hormones and neurotransmitters which affect the function of cardiac muscle and smooth muscle
• examples of a family of monoamines called catecholamines- causative agents to the fight or flight response
• they induce: increased heart rate, dilation of air passages, increase blood flow to skeletal muscle, release glucose from energy reserves

Question 10

What is parallel synthesis?

Answer 10

• a relatively small scale technique developed for the concurrent synthesis of large numbers of discrete single molecules
• makes use of multipath reaction carousels which typically have space for 6 or 12 reaction vessels

Question 11

What is combinatorial synthesis?

Answer 11

• less favoured but is still useful as a small scale technique developed to generate large numbers of different compounds concurrently
• technique usually generates mixtures of compounds that can lead to difficulties in discovering the identity of lead compound candidates

Question 12

What are synthetic libraries?

Answer 12

• libraries of compounds that can be used as a source of lead compounds

Question 13

What is the main issue associated with drug companies screening their own library when a new drug target has been selected and how is this issue resolved?

Answer 13

• the nature of a given companies previous research interests means that there libraries are often not very diverse and may contain many groups of structurally related compounds
• overcome by buying in libraries from specialist companies or academic institutions

Question 14

What are “Me Too” drugs?

Answer 14

• drugs already on the market often used by competitor companies as lead compounds in their own drug discovery programmes

Question 15

Define the term metabolism.

Answer 15

All the chemical reactions occurring in living systems

Question 16

What are the two main divisions of metabolism?

Answer 16

• primary metabolism

- secondary metabolism

Question 17

What is primary metabolism?

Answer 17

• concerned with the chemistry of essential life processes
• comprises a vast and complex web of chemical reactions commencing with carbon dioxide and leading to a diverse array of primary metabolites

Question 18

What is the metabolic map?

Answer 18

Charts all the major pathways whereby primary metabolites are interconverted in living cells

Question 19

What are the two main types of primary metabolic pathways?

Answer 19

• catabolic

- anabolic

Question 20

Define catabolism.

Answer 20

• theses processes involved the breakdown of large molecules into small ones
• they are degradative processes

Question 21

What is the purpose of catabolic processes?

Answer 21

• to provide energy for the energy requiring operations in cells
• to degrade the primary carbon sources ingested as food into starting materials for other biosynthetic pathways
• to convert waste materials into a form suitable for excretion from the cell or organism

Question 22

What is anabolims?

Answer 22

• processes that generate large or complex molecules from small ones
• these processes are synthetic

Question 23

What is the purpose of anabolic processes?

Answer 23

• provide the complex molecules required for building, maintaining and reproducing the living cell

Question 24

Describe the interrelationship between the two primary metabolic pathways

Answer 24

Catabolism service anabolism by providing starting materials and by providing energy

Question 25

What is secondary metabolism?

Answer 25

• concerned with the chemistry often unique to a particular organism of a small number of closely related organisms
• produces natural products called secondary metabolites
• they often have no apparent utility to the organisms concerned

Question 26

How are primary and secondary metabolism connected?

Answer 26

• primary metabolism from ides many of the small molecules utilised as building blocks in many secondary metabolic pathways

Question 27

What is an alkaloid?

Answer 27

• a naturally occurring nitrogenous organic compound
• usually basic in character
• excluding amino acids and nucleoside bases

Question 28

What is curare?

Answer 28

• South American Indian arrow poison
• kills intended prey by inducing paralysis of the respiratory muscles and subsequent asphyxiation
• the toxic components are not orally active
• only active via a direct wound or by injection

Question 29

What are the primary components of curare and hoe are they obtained?

Answer 29

• primary components are alkaloids
• obtained by crushing and cooking the roots and stems of one of two plants, chondrodendron tomentosum or strychnos toxifera

Question 30

What is the alkaloid component of curare principally responsible for its muscle relaxant properties?

Answer 30

Tubocurarine

Question 31

What is quinine?

Answer 31

• a derivative of 4-quinolinemethanol

- has an additional quinuclidine ring-system attached to the hydroxyl bearing carbon

Question 32

What is the most prevalent of the active alkaloid components from Peruvian bark?

Answer 32

Quinine

Question 33

Define the term pharmacokinetics.

Answer 33

Study of the time course of drug absorption, distribution, metabolism and excretion