Lecture 5 - QSAR 1

Question 1

What does it mean to quantify a structural-activity relationship?

Answer 1

Find a mathematical association between the biological activity of a drug and its physicochemical parameters, in the form of an equation

Question 2

What is the point of quantifying structural activity relationships?

Answer 2

During optimisation of a compound, it is more efficient to synthesise compounds based on a mathematical approach rather than randomly changing the structure

Question 3

What is IC50?

Answer 3

The concentration of a drug required to achieve 50% inhibition (e.g. of an enzyme, or growth)

Question 4

What is ED50?

Answer 4

The mean dose of a drug required to achieve a therapeutic effect in 50% of a test sample

Question 5

What are the 3 general structural modifications that can be made to a lead compound to produce analogues?

Answer 5

1. Size and shape of carbon skeleton
2. Nature and degree of substitution
3. Stereochemistry of lead compound (to do with chiral centres)

Question 6

What is usually the most important physicochemical parameter in terms of drug activity?

Answer 6

Hydrophobicity

Question 7

What is the equation for the partition coefficient in terms of logP? What log rule is used to achieve this?

Answer 7

log(x/y) = log(x) - log(y)

logP = log[drug]oct - log[drug]water

Question 8

Describe how an equation is found for the relationship between biological activity and hydrophobicity, and state what this equation is.

Answer 8

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

Question 9

When testing a larger range compounds, what shape does a graph of biological activity vs hydrophobicity take, and why is this?

Answer 9

Negative parabolic curve
At a certain point, increasing the hydrophobicity starts to decrease biological activity as the drug becomes trapped in fat deposits

Question 10

At what point on a graph is the maximum value for log(1/C), and how is the logP value for this point found?

Answer 10

Max value at logP0, when the gradient is zero

Find this by differentiating the equation, setting it to equal zero and solving for logP

Question 11

What are the 3 measures of hydrophobicity?

Answer 11

Partition coefficient (P) (or logP)
Distribution coefficient (D) (or logD)
The hydrophobic parameter (pi)

Question 12

What is the distribution coefficient (D) and why is it superior to the partition coefficient (P)?

Answer 12

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

Question 13

What is a limitation of using logP and logD to measure hydrophobicity?

Answer 13

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

Question 14

What is the equation for the hydrophobic parameter (pi)?

Answer 14

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

Question 15

What are 2 limitations of using the hydrophobic parameter (pi) values to calculate hydrophobicity?

Answer 15

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

Question 16

Why are the electronic effects of a drug important for affecting the biological activity?

Answer 16

Influences drug ionisation and polarity, which affects the chemical bonding it can partake in

Question 17

What constants are used to define the electronic effects for a substituent group?

Answer 17

If attached to an aromatic compound, use the Hammett substituent constant (sigma)
If attached to an aliphatic chain, use the rate of ester hydrolysis

Question 18

How are the Hammett substituent constant (sigma) values calculated?

Answer 18

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

Question 19

What is the equation for the Hammett substituent constant (sigma)?

Answer 19

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

Question 20

How does an electron withdrawing substituent, or an electron donating substituent affect the equilibrium constant of benzoic acid (k)?

Answer 20

If X is electron withdrawing, it stabilises the anion (ionised form) and increases k
If X is electron donating, k decreases

Question 21

What does a positive/negative sigma value indicate about the substituent?

Answer 21

Positive sigma = X is electron withdrawing

Negative sigma = X is electron donating

Question 22

Where on the structure of benzoic acid is the ortho, meta and para positions?

Answer 22

Clockwise from the functional group:
Ortho
Meta
Para

Question 23

How can the rate of ester hydrolysis tell you about the electronic effects of a substituent group?

Answer 23

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

Question 24

How do steric effects influence the biological activity of a drug?

Answer 24

Bulky substituents can act as steric shields to block intermolecular bonding
Or the increased surface area may increase the number of interactions

Question 25

What are the 3 approaches for quantifying steric effects

Answer 25

Taft steric parameter (Es)
Molar Refractivity (MR)
Verloop’s steric parameters

Question 26

How is Tafts steric parameter (Es) for different substituents calculated?

Answer 26

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

Question 27

What is the equation for calculating Tafts steric parameter (Es) for a substituent?

Answer 27

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

Question 28

How does the size of a substituent influence the value for Tafts steric parameter (Es)?

Answer 28

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

Question 29

What is molar refractivity and what is the equation for it?

Answer 29

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

Question 30

When calculating molar refractivity, why is the index of refraction important?

Answer 30

Tells you about the polarisability of a compound

Question 31

What is Verloop’s steric parameter and how is it calculated?

Answer 31

A computer calculates a steric value for a substituent using bond angles, van der Waals radii, bond lengths and conformations.

Question 32

In Verloop’s steric parameter, what are the dimensions of a substituent?

Answer 32

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

Question 33

Name 2 advantages of QSAR

Answer 33

1. Provides understanding of structure-activity relationships that may not be obvious from the raw data
2. Data sets can be interpolated (NOT extrapolated) to help make informed decisions regarding synthesis, which saves time and money

Question 34

Name 3 disadvantages of QSAR

Answer 34

1. Might assume false correlations as changing a single substituent often has hydrophobic, electronic and steric effects
2. Your data set might not be wide enough to ‘capture’ the best combination - the best answer might lie outside the range you have tested
3. Heavy reliance on biological data which is very error prone

Question 35

Why should you be wary of drugs with a logP value close to 2?

Answer 35

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…

Question 36

What is the difference between logP and ClogP?

Answer 36

logP is determined experimentally (aqueous/octanol partition coefficient)
ClogP is calculated by looking at a molecular structure and adding pi values from tables

Question 37

Why is the rate of ester hydrolysis constant (sigma i) not very reliable for predicting the electronic effects of a substituent?

Answer 37

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