Lecture 7 - Quantitative Structure Activity Relationships (QSAR) Flashcards
(15 cards)
What does the QSAR approach attempt to relate and how (give equation)?
- Biological activity of series of compounds to some measurable physicochemical property
- If correlation exists, equation can be drawn up to quantify relationship: log(1/c) = K1(logP) + K2 where y is activity and x is physicochemical property
What are the main 2 points about a QSAR study? (what systematic changes are involved, what are the influences on different properties)
- Usually study will involve single systematic variation at specific position on an aromatic ring, keeping all other substituents constant
- Influence of chemical substitution on a) hydrophobic b) electronic and c) steric properties is examined in approach
What does the partition coefficient measure and what is the equation?
- Experimentally measures hydrophobic nature of a drug
- P = conc. drug in octanol layer/conc. drug in aq. solution
Give an example of the biological activity equation for a specific drug and what the equation shows
- E.g. binding of drugs to serum albumin (determined by their hydrophobicity)
- Study of 40 compounds resulted in following equation: Log(1/C) = 0.75logP + 2.30 where y is biological effect
- Indicates serum albumin binding increases as logP increases
Why doesn’t activity increase indefinitely with lipophilicity? What may cause activity to decrease? What kind of shaped graph would be produced and what would the optimum lipophilicity be?
- If drug too hydrophobic, activity may be decreased by:
1. Poor absorption
2. Trapping in fat deposits
3. Hydrophobic drugs more susceptible to drug metabolism - Parabolic graph (curve goes up then down)
- Maximum of graph = logP^0 (optimum value)
What do the substituent hydrophobicity constants (pi) measure? How is it obtained/measured? What is the equation?
- Measure of how hydrophobic a substituent is relative to hydrogen
- Partition coefficient measured for a standard compound with and without substituent
- pi(x) = logP(x) - logP(H) where P(H) is for standard compound and P(x) = is for standard compound with substituent (x = group or atom)
What does a positive value of substituent hydrophobicity constant mean? Give an example.
- Substituent (i.e. Cl) makes compound (i.e. benzene) more hydrophobic (Cl is more hydrophobic than H on benzene ring)
What is the difference between logP and pi?
LogP measures a drug overall whereas pi measures hydrophobicity of particular region on candidate drug molecule
What is the Hammett constant (sigma) a measure of? How are values obtained? What is the equation? What position are the substituents in?
- Measure of electron withdrawing/donating ability of substituent
- Values obtained by considering effects groups have on ionisation of benzoic acid
- sigma (x) = logK(x)/K(H) = logK(x) - logK(H)
- sigma (x) -ve for EDGs, +ve for EWGs
- Functional group at meta- and para- positions on Ar ring of benzoic acids to avoid steric interactions
What is the dissociation constant equation for benzoic acid? What would the effect of an EWG be on the position of the equilibrium of K(H) and why? (Same question with an EDG)
- Eqm. set up between ionised and non-ionised forms and proportions are known as eqm./dissociation constant: K(H) = [PhCO2]-/[PhCO2H] where H indicates derivative unsubstituted
- EWG shifts eqm. right so benzoic acid derivative is a stronger acid
- EDG shifts eqm. left so weaker acid obtained
What does the Taft Steric Parameter relate? What is the symbol?
- Importance and shape and size (bulk)
- Given by symbol Es
What is molar refractivity (MR)? How is it calculated?
- Describes volume occupied by compound and how easily it is polarised
- Additive parameter so MR for a molecule calculated by adding MR values together for drug molecule’s constituent parts
Hansch equation
Log(1/C) = K1logP + K2σ + K3Es + K4
Log(1/C) = Activity
K1logP = Lipophilicity
K2σ = Electronic effects
K3Es = Steric effects
K4 = constant
What is the Craig plot used for? What is on each axis? What are the advantages of it?
Used to visualise relative properties of different substituents
- y = value of σ factor
- x = value of π factor
Advantages:
1. Shows there is no relationship between σ and π
2. Possible to tell at a glance which substituents have +ve/-ve σ and π values
3. Easy to see which substituents have similar π fragments e.g. CF3SO2, CF3 and Br will produce similar effects on activity
4. Once equation plotted, shows whether σ or π should be +ve/-ve for good bio activity
What is the Topliss Scheme? Give an example of how it works.
- Diagram that allows medicinal chemist to choose what substituents to place in Ar ring of lead compound
- First, prepare 4-chloro analogue of lead
- If 4-chloro analgue more potent than lead, next analogue to prepare is 3,4-dichloroanalogue (follow M branch)
- If 3,4-dichloro analogue more active, prepare next analogue 3-CF3-4-Cl (follow M branch)
