Natural Products In Drug Discovery Flashcards
What are the 5 key requirements of an orally administered drug?
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
What happens if the drug is too hydrophilic?
It will be unable to pass rough the cell membrane of the gut wall because the lipid bilayer is hydrophobic
What happens if the drug is too lipophilic?
It will be insufficiently water soluble to gain good contact with the gut wall
What is Lipsinki’s rule of 5?
1) the drug candidate must have a molecular weight of
What is the process of a lead discovery?
- 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
What is the final part of the lead discovery process?
Discovery of a lead compound which possesses the desired pharmacological activity and which represents starting point of subsequent drug design and development
What are two sources of potential lead compounds?
- structural alteration of the natural substrate or ligand
- natural enzyme or ligand substrate for a receptor
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.
-adrenaline and noradrenaline used to develop salbutamol (asthma) and dobutamine (heart failure)
What effects do adrenaline and noradrenaline have on the body?
- 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
What is parallel synthesis?
- 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
What is combinatorial synthesis?
- 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
What are synthetic libraries?
- libraries of compounds that can be used as a source of lead compounds
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?
- 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
What are “Me Too” drugs?
- drugs already on the market often used by competitor companies as lead compounds in their own drug discovery programmes
Define the term metabolism.
All the chemical reactions occurring in living systems
What are the two main divisions of metabolism?
- primary metabolism
- secondary metabolism
What is primary metabolism?
- 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
What is the metabolic map?
Charts all the major pathways whereby primary metabolites are interconverted in living cells
What are the two main types of primary metabolic pathways?
- catabolic
- anabolic
Define catabolism.
- theses processes involved the breakdown of large molecules into small ones
- they are degradative processes
What is the purpose of catabolic processes?
- 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
What is anabolims?
- processes that generate large or complex molecules from small ones
- these processes are synthetic
What is the purpose of anabolic processes?
- provide the complex molecules required for building, maintaining and reproducing the living cell
Describe the interrelationship between the two primary metabolic pathways
Catabolism service anabolism by providing starting materials and by providing energy
