Target based drug discovering and administration

Question 1

How will you find a molecule for a particular target?

Answer 1

• Variation of the molecules the protein binds to in nature - either the enzyme substrate or the molecule whihc binds to a receptor
• Modifications can make the drug stimulate the receptors signalling (agonist) or disrupt it (antagonist) depending on how it binds
• Crystal structures of the target proteins can provide information about where modifications might be effective
• Looks similar to the enzyme substrate but has been rearranged so that it can still bind but wont be destroyed by the enzyme

Question 2

Ways of working out the structure to fit the target

3 ways

Answer 2

• Docking = calculate where and how well a molecule binds to the target, often using a large virtual library of compounds which could be synthesised
• Binding site mapping = creating a model illustrating where arrangement of intermolecular interactions can be addressed
• De novo drug design = ask the computer to generate a molcecule which could bind in the chosen site

Question 3

Designed synthetic compounds

Benefits and drawbacks

Answer 3

• Benefits: synthesis straightforward (comparatively), readily modified at any point to tune properties, mechanism of action usually well understood
• Drawbacks: limited to moelcules which are easily made, chirality and larger 3D structures rarer, does not work so well on proteins without small molecule binding pockets

Question 4

Screening and selection

What is it and its benefits and drawbacks

Answer 4

• Unbiased approches take a huge random library of different compounds
• Screening: measure each molecule’s interaction with the target
• Selection: use some affinity measurement to separate binders from non-binders
• Benefits: tests million of molecules at once, could uncover unexpected activities, exploit molecular biology techniques, target any protein with larger molecules
• Drawbacks: might not find good hits, limited to libaries which can easily be made, larger molecules may have trouble getting through membranes

Question 5

What does in vitro and in vivo mean?

Answer 5

• In vitro = on isolated cells, tissues and proteins, usually preferred for inital tests because it is cheaper, quicker, less controversial and can be automated, will test whether the drug engages its target in what fashion and whether it changes the targets activity or kills the cell
• In vivo = on entire organisms, permformed on a smaller selection of compounds, will uncover information about systemic toxicity, absorption, distribution, metabolism and excretion

Question 6

Hit-to-lead and lead optimisation

Answer 6

• Hit-to-lead: compounds from the library are short-listed according to synthetic accessibility, specificity, toxicity and physical properties - looking at how to make them
• Lead optimisation: the compound will be optimised for physiochemcial properties (polarity, molecular weight, HBs), ADME, and toxicity - looking at how it is going to affect as a whole

Question 7

Clinical trials

Answer 7

1. Phase 1: all about safety, people do not have the disease in question, just looking to see if there are any effects
2. Phase 2: patients who have the disease, still looking at safety but now looking to see if it improves the patients life, half will be given placebo and half will be given the real drug
3. Phase 3: using more people over many sites over the world so that you have fully represented the whole population, will be compared to the current treatment to see if it is better

Question 8

What is pharmacokinetics and pharmacodynamics?

Answer 8

• Pharmacokinetics: how does the body deal with the drug, how the drug moves through the body in the processes of ADME
• Pharmacodynamics: what effect does the drug have on the body, the study of how a drug binds to its binding site

Question 9

Administration - local routes

Answer 9

1. Topical - external application of the drug on the surface (lotion, cream, spray)
2. Deeper tissues - certain deep areas can be approached by syringe and needle
3. Arterial supply - closed intra aterial injection

Question 10

Systemic routes

Answer 10

1. Oral
2. Sublingual
3. Inhalation
4. Intradermal and subcutaneous
5. Intravenous

Question 11

Sublingual

Answer 11

• Kept under the tongue or crushed and spread over the mouth
• Absorption through mucous membrane with good access to arteries
• Advantages: rapid absorption, liver is by passed (directly in the systemic circulation), unconscious patients can be given it
• Disadvantages: only lipid and saliva soluble drugs, uncooperative patients cant be given it, irritate the muscosa

Question 12

Intravenous

Answer 12

• Going directly into the vein
• Advantages: quick action, desired concentration easily obtained, no hepatic first pass metabolism, unconscious and uncooperative patients
• Disadvantages: costly, local irritation, self medication not possible, action cannot be stopped
• Very fast (onset of action between 15-30 seconds)

Question 13

Intradermal, subcutaneous and intramuscular

Answer 13

• Intradermal - in between the layers of skin
• Subcutaneous - self injection possible, below the skin but not yet at muscle
• Intramuscular - into the muscle
• Slightly slower (onset of action between 10-30 minutes)

Question 14

Oral

Answer 14

• Advantages: self medication possible, large area for absorption, slow action (safe for some risky drugs), can be solid or liquid forms of the drug
• Disadvantages: irritant and unpalatable drugs cannot be adminsitered, may induce nausea and vomiting, not useful if vomiting or diarrhoea is present or patient unconscious, can be destroyed by gastric juices

Question 15

Lipinksi’s Rule of 5

Answer 15

For something to be orally active it must have:
* < 5 HBD (usually NH and OH)
* < 10 HBA (all N and O atoms)
* Molecular weight < 500
* Octanol-water partition coefficient (log P < 5)