Methods of Drug Discovery - Statins (4)

Question 1

Ethnopharmacology

Answer 1

• Study of the use of plant derived materials in traditional societies to maintain and improve health
• This can lead to a new drug

Question 2

Screening

Answer 2

• can use an available biological screen to discover a lead structure

Question 3

Biochemistry of a disease

Answer 3

• developing a bio-assay and then screening a library of compounds for activity

Question 4

Statins

Answer 4

Cholesterol lowering drugs

- To get this, we needed to understand the biosynthesis of cholesterol

Question 5

Familial Hypercholesterolemia

Answer 5

• genetic disorder causing high bad cholesterol levels(LDL) in blood which ultimately results in early cardiovascular disease at age 30-40
• prevents efficient removal of cholesterol (receptors not working) – build up

Question 6

Is cholesterol good for the body?

Answer 6

YES biosynthesized in all animals – not too much not too little typa thing

Question 7

How to approach a problem like cholesterol lowering diseases?

Answer 7

• UNDERSTAND everything that it does in the body
• see if you can interfere with the metabolism rate or biosynthesis
• inhibit enzyme that helps produce cholesterol in RDS

Question 8

Biosynthesis of Cholesterol; enzyme in RDS

Answer 8

HMG reductase enzyme mediates RDS…

Question 9

How to inhibit an enzyme in general?

Answer 9

Find or create a molecule with a similar structure that is expected to bind to this specific enzyme that can reduce its efficacy or inhibit completely

Question 10

Akira Endo; What did he find? What did it contain? Toxicity?

Answer 10

• fungi that ward off parasitic organisms by inhibiting their cholesterol synthesis
• cell membranes of fungi had ergosterol instead of cholesterol – allows them to do this
• Mevastatin isolated - very good but showed toxicity
  Instead; oyster mushroom

Question 11

What happens when a compound is amazing but shows toxicity?

Answer 11

• Find out what parts of compound is crucial and what parts are just decoration… Find out what can be replaced. (substituents, polarity, bio availability, metabolic stability)
• SYNTHESIS of new drugs
• remove hydrophobic pieces… can’t get through body!

Question 12

High EN or Fluorine properties (2)

Answer 12

1. Slows down enzyme mechanism – Increased lipophilicity
2. Makes rings less likely of attracting OH groups (oxidation) –> so the drug stays in the body much longer - avoids metabolism