Lecture 5 - QSAR 1 Flashcards
What does it mean to quantify a structural-activity relationship?
Find a mathematical association between the biological activity of a drug and its physicochemical parameters, in the form of an equation
What is the point of quantifying structural activity relationships?
During optimisation of a compound, it is more efficient to synthesise compounds based on a mathematical approach rather than randomly changing the structure
What is IC50?
The concentration of a drug required to achieve 50% inhibition (e.g. of an enzyme, or growth)
What is ED50?
The mean dose of a drug required to achieve a therapeutic effect in 50% of a test sample
What are the 3 general structural modifications that can be made to a lead compound to produce analogues?
- Size and shape of carbon skeleton
- Nature and degree of substitution
- Stereochemistry of lead compound (to do with chiral centres)
What is usually the most important physicochemical parameter in terms of drug activity?
Hydrophobicity
What is the equation for the partition coefficient in terms of logP? What log rule is used to achieve this?
log(x/y) = log(x) - log(y)
logP = log[drug]oct - log[drug]water
Describe how an equation is found for the relationship between biological activity and hydrophobicity, and state what this equation is.
Synthesise a few analogues
Measure the biological activity (C) and calculate the partition coefficient (P) for each
Plot log(1/C) against logP
Find a line of best fit using linear regression analysis
log(1/C) = (k1 x logP) + k2
When testing a larger range compounds, what shape does a graph of biological activity vs hydrophobicity take, and why is this?
Negative parabolic curve
At a certain point, increasing the hydrophobicity starts to decrease biological activity as the drug becomes trapped in fat deposits
At what point on a graph is the maximum value for log(1/C), and how is the logP value for this point found?
Max value at logP0, when the gradient is zero
Find this by differentiating the equation, setting it to equal zero and solving for logP
What are the 3 measures of hydrophobicity?
Partition coefficient (P) (or logP) Distribution coefficient (D) (or logD) The hydrophobic parameter (pi)
What is the distribution coefficient (D) and why is it superior to the partition coefficient (P)?
LogD is the partition coefficient (logP) at a certain pH
Usually at physiological pH (7.4)
This is because at certain pH’s a drug becomes ionised, which changes the hydrophobicity
Therefore it is known as pH-dependent whereas logP is pH-independent
What is a limitation of using logP and logD to measure hydrophobicity?
You need to synthesise a few random compounds first and calculate their log(1/C) and logP, to find the mathematical relationship. Your starting point may be way off the optimum logP
What is the equation for the hydrophobic parameter (pi)?
Pi = (logPx) - (logPH)
Where x = the compound with the substituent
and H = the original compound
So Pi is essentially the contribution of that substituent to the hydrophobicity of the drug
What are 2 limitations of using the hydrophobic parameter (pi) values to calculate hydrophobicity?
The pi value will vary depending on whether the substituent is attached to an aliphatic or aromatic system. They are not true constants
The pi value will also vary depending on which source you use
Why are the electronic effects of a drug important for affecting the biological activity?
Influences drug ionisation and polarity, which affects the chemical bonding it can partake in
What constants are used to define the electronic effects for a substituent group?
If attached to an aromatic compound, use the Hammett substituent constant (sigma)
If attached to an aliphatic chain, use the rate of ester hydrolysis
How are the Hammett substituent constant (sigma) values calculated?
Benzoic acid exists in equilibrium between ionised/non-ionised forms Adding a substituent (X) will shift the equilibrium depending on whether it is electron withdrawing or electron donating Measure k (the equilibrium constant) for benzoic acid with and without the substituent
What is the equation for the Hammett substituent constant (sigma)?
Sigma(X) = logKx - logKH
where Kx is the equilibrium constant of benzoic acid with the substituent and
KH is the equilibrium constant of benzoic acid without the substituent
How does an electron withdrawing substituent, or an electron donating substituent affect the equilibrium constant of benzoic acid (k)?
If X is electron withdrawing, it stabilises the anion (ionised form) and increases k
If X is electron donating, k decreases
What does a positive/negative sigma value indicate about the substituent?
Positive sigma = X is electron withdrawing
Negative sigma = X is electron donating
Where on the structure of benzoic acid is the ortho, meta and para positions?
Clockwise from the functional group:
Ortho
Meta
Para
How can the rate of ester hydrolysis tell you about the electronic effects of a substituent group?
Electron-donating groups reduce rate of hydrolysis, giving a negative sigma-i value
Electron-withdrawing groups increase the rate of hydrolysis, giving a positive sigma-i value
How do steric effects influence the biological activity of a drug?
Bulky substituents can act as steric shields to block intermolecular bonding
Or the increased surface area may increase the number of interactions
What are the 3 approaches for quantifying steric effects
Taft steric parameter (Es)
Molar Refractivity (MR)
Verloop’s steric parameters
How is Tafts steric parameter (Es) for different substituents calculated?
The rate of acid catalysed-hydrolysis of a reference ester (usually just with H attached), and the ester with the substituent attached.
The rate of hydrolysis = k
What is the equation for calculating Tafts steric parameter (Es) for a substituent?
Es = logkRCOOX - logkRCOOH
The first logk is the log of the rate constant for the ester containing the substituent group of interest
The second logk is the log of the rate constant for the reference ester. This is usually RCOOH but can sometimes be RCOOMe. Important to check
How does the size of a substituent influence the value for Tafts steric parameter (Es)?
If the substituent is smaller than the substituent used in the reference ester, hydrolysis will be faster and Es will be positive
If the substituent is larger than the substituent used in the reference ester, hydrolysis will be slower and Es will be negative
What is molar refractivity and what is the equation for it?
A measure of the volume of a given substituent MR = (n2-1)/(n2+2) x MW/d Where: n=index of refraction MW = molecular weight d = density MW/d = molar volume
When calculating molar refractivity, why is the index of refraction important?
Tells you about the polarisability of a compound
What is Verloop’s steric parameter and how is it calculated?
A computer calculates a steric value for a substituent using bond angles, van der Waals radii, bond lengths and conformations.
In Verloop’s steric parameter, what are the dimensions of a substituent?
L = length along axis of the bond that joins the substituent to the parent molecule B1-4 = four width parameters at right angles to the axis L viewed in cross section
Name 2 advantages of QSAR
- Provides understanding of structure-activity relationships that may not be obvious from the raw data
- Data sets can be interpolated (NOT extrapolated) to help make informed decisions regarding synthesis, which saves time and money
Name 3 disadvantages of QSAR
- Might assume false correlations as changing a single substituent often has hydrophobic, electronic and steric effects
- Your data set might not be wide enough to ‘capture’ the best combination - the best answer might lie outside the range you have tested
- Heavy reliance on biological data which is very error prone
Why should you be wary of drugs with a logP value close to 2?
The blood brain barrier has a logP of 2. So drugs close to this value will pass it easily. Good if you want to access the CNS, bad if you don’t…
What is the difference between logP and ClogP?
logP is determined experimentally (aqueous/octanol partition coefficient)
ClogP is calculated by looking at a molecular structure and adding pi values from tables
Why is the rate of ester hydrolysis constant (sigma i) not very reliable for predicting the electronic effects of a substituent?
The steric effects of the substituent will also have a big effect on the rate of ester hydrolysis. So cannot be sure the effects are entirely attributable to the electronic effects
