Improving Drugs/Drug Optimisation

Question 1

What is improving drugs/drug optimisation?

Answer 1

This process involves changing the atoms and the arrangement of atoms to change some or all of the properties of the drug.

Question 2

What properties of a drug can be changed by drug optimisation?

Answer 2

• Pharmacokinetics.
• Physiochemical properties.
• Side effect profile.
• Binding affinity.

Question 3

Drug optimisation is a cyclic process, featuring which four sub-processes?

Answer 3

Analyse, design, make, test.

Question 4

Give some of the desired properties of improved drugs.

Answer 4

• Simplicity allowing for mass production.
• Inexpensive production.
• Ideally able to be made into tablets – orally bioavailable.
• Specificity to the desired receptor/avoiding off-target activity.
• Predictable polymorphism.
• Good solubility.
• Good ADME profile.
• Once-a-day dosing.

Question 5

Describe the relationship between affinity and pharmacokinetics.

Answer 5

Affinity and pharmacokinetics are often at odds with each other and the optimisation of both is like a tug of war; improving one has a negative effect on the other. A balance must be sought between the two.

Question 6

Describe the two phases of drug optimisation.

Answer 6

Drug optimisation has two phases; hit-to-lead and the full medicinal chemistry project. Hit to lead is a rapid process using fast techniques such as parallel synthesis and a full medicinal chemistry project is a slower process using a single synthesis.

Question 7

What is structure-based drug design?

Answer 7

SBDD uses knowledge of the receptor structure to guide the design of new compounds able to exploit unfulfilled extractions and shape complementarity.

Question 8

What is ligand-based drug design?

Answer 8

LBDD uses knowledge of ligand structure with or without knowledge of the receptor to create models based on structural properties able to discriminate good compounds from bad.

Question 9

What is fragment-based drug design?

Answer 9

FBDD is the process by which high concentration samples of a pure target are mixed with small fragments of chemical entities. They are then assayed by sophisticated methods and then enlarged and modified rationally, with additions made around the target.

Question 10

Describe the rule of three that is used to guide the selection of fragments used is fragment-based drug design.

Answer 10

Selection of fragments should follow the rule of three:
• A molecular weight of <300.
• The number of hydrogen bond donors is ≤3.
• The number of hydrogen bond acceptors ≤3.
• CLogP is ≤3.
• Ideally NROT ≤3.
• Ideally PSA ≤3.