QSAR

Question 1

what is De Novo drug design and what two things are used to help with drug design?

Answer 1

• it a design requiring knowledge of potential drug target

- uses QSAR and molecular modelling to help design the drug.

Question 2

what are molecular descriptors?

Answer 2

• hydrophobicity
• steric bulk
• electronic effect

Question 3

what interactions do drug and targets have?

Answer 3

1. covalent
2. hydrophobic
3. van der Waals
4. H-bonds
5. electrostatic
6. pi-stacking
7. combinations

Question 4

what is QSAR?

Answer 4

the relation of the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula.

Question 5

what are the common physicochemical properties of drugs?

Answer 5

1. hydrophobicity of a molecules
2. hydrophobicity of substituents
3. electronic properties of substituents
4. steric properties of substituents

Question 6

what factors increase drug binding?

Answer 6

1. increased logP

2. greater hydrophobicity

Question 7

what logP value causes molecule to enter the CNS?

Answer 7

2.3

Question 8

why do we alter logP values of drugs away from 2.0?

Answer 8

because drugs with loP of around 2.3 can enter the CNS easily. So altering logP reduces the CNS side effects of the drug.

Question 9

what is the substituent hydrophobicity constant?

Answer 9

• a measure of the substituents hydrophobicity relative to hydrogen.
• identifies substituents that might interact with hydrophobic regions in binding site

Question 10

what does a positive and negative hydrophobicity constant value mean?

Answer 10

positive: substituents are more hydrophobic than H
Negative: substituents are less hydrophobic than H

Question 11

when the substituent is an electron withdrawing group, is the hammett constant positive or negative?

Answer 11

hammett constant is positive

Question 12

when the substituent is an electron donating group, is the hammett constant positive or negative?

Answer 12

hammett constant is negative

Question 13

what does molar refractivity measure?

Answer 13

the effective volume of substituents

Question 14

What two things does a QSAR equation relate together?

Answer 14

the physicochemical properties to the biological activity of a series of compounds

Question 15

what three factors are included in a QSAR equation?

Answer 15

1. LogP
2. Hammett Substituent Constant
3. Molar Refractivity

Question 16

what happens to the activity of a drug if it has a positive hydrophobic substituent constant?

Answer 16

activity increases

Question 17

what happens to the activity if a drug is it has a negative hammett substituent constant?

Answer 17

activity increases

Question 18

three factors that increase drug activity?

Answer 18

1. an increase in logP (so more hydrophobicity)

2. negative hammett substituent values (i.e. electron donating substituents)

Question 19

what is the craig plot useful for?

Answer 19

• allows an easy identification of suitable substituents for a QSAR analysis including both relevant properties (hammett and logP)
• so you pick a subsituent from different parts of the quadrat to ensure orthogonality (variation).

Question 20

what two substituent selection processes are available?

Answer 20

1. craig plot

2. topliss tree

Question 21

what is a pro of using the topliss decision tree?

Answer 21

-it aids you to think about the substituent parameters and put them in order.

Question 22

what are bioisosteres?

Answer 22

substituents with comparative physicochemical properties

Question 23

what us free-Wilson QSAR?

Answer 23

a measure of the biological activity of the parent structure and comparing this with the activity of analogues bearing different substituents