MDD Overview

Question 1

what is a patent?

Answer 1

A legal protection of a discovery

Question 2

How long can a patent last for?

Answer 2

20 years

Question 3

What are the first ten years in industry spent doing?

Answer 3

research!

Question 4

How can a patent be extended? if so how long for?

Answer 4

can be extended up to another 5 years under a supplementary protection certificate if the drug has been found to be viable for a new indication

Question 5

1. What do we do if there is no known 3D Structure and No known ligands !?

Answer 5

Combinatorial chemistry can be used to make several thousand compounds in a single process.

High throughput screening - biological assay of a large number of chemicals

Question 6

What can be done if there is no known 3D structure, BUT the ligands are known

Answer 6

We do a pharmacophore search and QSAR studies

Question 7

What do we do if the 3D stucture is known but the ligands are not known?

Answer 7

De novo design - build a ligand based on 3D structure.

Virtual Screening - using computer based models to identify molecules that are most likely to bind to an enzyme or a receptor

Question 8

What do we do if the 3D stucure is known and the ligands are known?

Answer 8

Structure based design

Question 9

Combinatorial chemistry can be used to make several thousand compounds in a single process.

High throughput screening - biological assay of a large number of chemicals

Answer 9

1. What do we do if there is no known 3D Structure and No known ligands !?

Question 10

We do a pharmacophore search and QSAR studies

Answer 10

What can be done if there is no known 3D structure, BUT the ligands are known

Question 11

De novo design - build a ligand based on 3D structure.

Virtual Screening - using computer based models to identify molecules that are most likely to bind to an enzyme or a receptor

Answer 11

What do we do if the 3D stucture is known but the ligands are not known?

Question 12

Structure based design

Answer 12

What do we do if the 3D stucure is known and the ligands are known?

Question 13

State 6 key principles of drug design (6marks)

Answer 13

1. Drugs and receptors must have complimentary distribution of functional groups to maximise Hydrogen bonding and Electostatic interactions
2. Hydrogen bonds have a specific role to play in specificity (binding) but not affinity (attraction)
3. Charged groups have a significant role to play in both specificty and affinity
4. Drugs must have a complimentary size and shape to maximise VDW
5. VDW has a contribution to affinity but not specificity
6. Conformationally constrained molecules are more likely to be potent than unconstrained ones

Question 14

what problems are associated with drug design?

Answer 14

the drug should be cheap (but isnt)

chemically stable

should be potent

lipophillic but still water soluble

stable against enzymes

Question 15

How to improve drug affinity?

Answer 15

You need:

1. Large surface area of interaction
2. Numberous hydrogen bonds and electrostatic interactions
3. A drug with polar group, but not too polar where it is absorbed poorly.

Question 16

write down gibbs equation of free energy

Answer 16

delatG = deltaH - TdeltaS

Where deltaH = enthalpy change

deltaS = change in entropy as a function of temperature

Question 17

what is the entropy of a molecule defined by?

Answer 17

Defined by its freedom of translational, rotational movement and freedom of conformational change

Question 18

What is the ideal characteristics for drugs in terms of entropy?

Answer 18

The drug-receptor complex must be enthalpically equivalent to the water-receptor complexes, so not to reduce entropy which is undesirable

The newly formed complex must also be enthalpically superior when the electrostatic interactions (if any) are made.

Question 19

what is a lead compound? And state where they come from

Answer 19

1. First compound or structural motif of a new family of therapeutic agents to be discovered.
2. Rarely the actual drug structure that will be marketed or go to clinical trials
3. Protected by patent

They Can be found by:

• Screening of synthetic or natural compounds (imatinib)
• Natural products (Aspirin)
• Side effects (viagra)
• Metabolism studies (estrogen)
• Serendipity (Penicillin)
• Rational Drug design (tramadol)

Question 20

outline how to screen for hits:

Answer 20

First coose therapeutic area its ‘target’

target may be a protein or nucleic acid

choose and develop assay (High-throughput)

choose molecules form libraries too

carry out screen and analyse data for ‘hits’

develop ‘hit’ to ‘lead’ by chemical synthesis

Question 21

what would we look for in a primary screen?

Answer 21

molecules that target the biological stuctures. e.g Enzyme-based, cell based etc used in a well