Drug design: Sources of drugs

What is a lead compound?

A compound that interacts with the biological process under study.

What are issues surrounding lead compounds?

They are not the most active compound and they may have severe side effects.

What do lead compounds require to become useful drugs and why?

Require a design process in order to become more active and less toxic.

What are the approaches to finding a lead compound?

- Natural products.

- Rational design e.g., natural ligands, enzyme structures.

- Library screening.

- Side effects of existing drugs.

Describe medical folklore in the context of natural products and finding a lead compound.

Screening of medical folklore leads to finding of novel and complex structures which have difficult pharmaceutical properties e.g., low solubility. Also difficult to synthesise and manufacture.

Describe plants and trees in the context of natural products and finding a lead compound.

Some of the best known drugs such as aspirin and morphine are from plants.

Describe microorganisms in the context of natural products and finding a lead compound.

Bacteria, viruses and fungi have led to production antibiotics produced by fermentation and post-synthetic modification.

Describe animal life in the context of natural products and finding a lead compound.

Animal venom has been used to find lead compounds. Sea life such as sponges and coral have shown to have anticancer and antiviral activity.

Describe exploiting natural ligands in the context of the rational approach and finding a lead compound.

The modification of natural agonists or antagonists have led to the development of lead compounds.

Describe screening of existing libraries when finding lead compounds.

Pharma companies have vast libraries which they can look through and adapt existing compounds.

Describe exploiting side effects of existing drugs to find lead compounds.

Side effects of specific drugs can help treat other conditions e.g., sulfa antibiotics have a side effect of lowering blood glucose level which is a useful effect when treating type 2 diabetes.

What does identifying a SAR/Pharmacophore lead too?

The production of analogues which allow identification of vital parts of a molecule. Also allows synthetic simplification and enhanced activity through additional intercations.

How can the pharmacokinetics of a lead compound be improved?

Through Lipinski's rule of 5 which are the ideal characteristics of a drug for oral delivery.

What is Lipinski's Rule of 5?

- No more than 5 hydrogen bond donors

- No more that 10 hydrogen bond acceptors

- A molecular weight under 500

- A log P value under 5.0

How can alteration of pharmacokinetics make a difference to patients?

By:

- Reducing dosing levels.

- Improved duration of action.

- Providing a better mode of application.

What can affect the development of a manufacturing process?

Economy - Availability of reactants and reagents as well as plant specifications.

Safety - Physical safety as well as toxicity of environment.