QSAR Flashcards
what is De Novo drug design and what two things are used to help with drug design?
- it a design requiring knowledge of potential drug target
- uses QSAR and molecular modelling to help design the drug.
what are molecular descriptors?
- hydrophobicity
- steric bulk
- electronic effect
what interactions do drug and targets have?
- covalent
- hydrophobic
- van der Waals
- H-bonds
- electrostatic
- pi-stacking
- combinations
what is QSAR?
the relation of the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula.
what are the common physicochemical properties of drugs?
- hydrophobicity of a molecules
- hydrophobicity of substituents
- electronic properties of substituents
- steric properties of substituents
what factors increase drug binding?
- increased logP
2. greater hydrophobicity
what logP value causes molecule to enter the CNS?
2.3
why do we alter logP values of drugs away from 2.0?
because drugs with loP of around 2.3 can enter the CNS easily. So altering logP reduces the CNS side effects of the drug.
what is the substituent hydrophobicity constant?
- a measure of the substituents hydrophobicity relative to hydrogen.
- identifies substituents that might interact with hydrophobic regions in binding site
what does a positive and negative hydrophobicity constant value mean?
positive: substituents are more hydrophobic than H
Negative: substituents are less hydrophobic than H
when the substituent is an electron withdrawing group, is the hammett constant positive or negative?
hammett constant is positive
when the substituent is an electron donating group, is the hammett constant positive or negative?
hammett constant is negative
what does molar refractivity measure?
the effective volume of substituents
What two things does a QSAR equation relate together?
the physicochemical properties to the biological activity of a series of compounds
what three factors are included in a QSAR equation?
- LogP
- Hammett Substituent Constant
- Molar Refractivity
what happens to the activity of a drug if it has a positive hydrophobic substituent constant?
activity increases
what happens to the activity if a drug is it has a negative hammett substituent constant?
activity increases
three factors that increase drug activity?
- an increase in logP (so more hydrophobicity)
2. negative hammett substituent values (i.e. electron donating substituents)
what is the craig plot useful for?
- 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).
what two substituent selection processes are available?
- craig plot
2. topliss tree
what is a pro of using the topliss decision tree?
-it aids you to think about the substituent parameters and put them in order.
what are bioisosteres?
substituents with comparative physicochemical properties
what us free-Wilson QSAR?
a measure of the biological activity of the parent structure and comparing this with the activity of analogues bearing different substituents
