#qsar

senior officers of the Hounds of Pax chapter

Qasr el Baron, Heliopolis, Cairo, Egypt,

The Baron Empain Palace (Qasr el Baron, or The Palais Hindou) is a distinctive and historic mansion in Heliopolis, a suburb northeast of central Cairo, Egypt.

The palace was designed by French architect Alexandre Marcel and decorated by Georges-Louis Claude. Inspired by the Angkor Wat in Cambodia, it was built between 1907 and 1911, in reinforced concrete.

QSAR modelling predicts the biological activity of a compound based off its physical properties. They are used to avoid synthesising and testing every possible version of a molecule to find the optimum for bioactivity. A small number of structurally similar molecules are synthesised and tested, and these results are used to mathematically predict other similar molecules on a computer.

Hydrophobicity 

This dictates the ease at which a molecule will pass through a cell membrane. Too hydrophobic and the molecule will be drawn to lipids and its bioactivity will be reduced, too hydrophilic and the molecule will be too polar to pass through the phospholipid bilayer and will not carry out its desired activity (will be excreted in urine)

LogP - a measure of the whole molecule’s hydrophobicity 

High logP = more hydrophobic

Low logP = more hydrophillic (polar)

Optimum for bioavailibility = 2-4.5

A regression equation can be formed with c=concentration for max activity

1/c = K1 logP + k2

If linear, values for other similar structures can be taken off the line. If parabolic = logP^2, indicating that after a max concentration bioavalibility will not increase as the drug becomes too hydrophobic and moves into fats.

Substituent hydrophobicity constant,  π

Measures the hydrophobicity of individual substituents in a compound.

π = logPX - logPH

X= partition coefficient for substituted compound 

H= partition coefficient for unsubstituted compound (Hydrogen (so if H was in place of the substituent of interest))

Compares how hydrophobic a substituent is compared to hydrogen

π = +ve --> X= more hydrophobic than hydrogen

π = -ve --> X= less hydrophobic than hydrogen

Note: can be used to calculate logP by adding substituents, rather than having to synthesise and test the molecule (clogP = calculated logP)

Electronics

Pharmacokinetics (administration, distribution, metabolism and excretion) rarely depends on hydrophobicity alone. The polarity of a compound dictates its passage through the patient and its binding at point of activity.

Hammett substituent constant, σ

The starting point  is a chemical equilibrium for which both the substituent constant and the reaction constant are arbitrarily set to 1: the ionization of benzoic acid (R and R' both H) in water at 25 °C.

Provides K0.

RCO2H <--> RCO2- + H+

uses the dissociation constant

kH = [RCO2-][H+] / [RCO2H]

If X is electron withdrawing, it will stabilise RCO2- and shift the equilibrium to the right. kX will increase

eg NO2, CN, Cl --> +ve  σ

If X is electron donating, it will destabilise the RCO2- anion and shift equilibrium to the left, with a drop in kX.

eg alkyls, ethyls, methyls = -ve  σ

σ = logkX - logkH

Steric properties 

Taft steric parameter, Es = rate of hydrolysis of XCH2CO2Me under acidic conditions

Es = logkX - logKH

If X is physically small, the rate of hydrolysis (time taken to reach tetrahedral intermediate) will be fast.

Here, the size of R affects the rate of reaction by blocking nucleophilic attack by water.

           H             1.24 +ve value: little steric resistance to hydrolysis          Me             0.00 the reference substituent in the Taft equation          t-Bu          -2.78 -ve value: large resistance to hydrolysis

Small X = large Es, large X = small Es

Accuracy of calculation decreases as the bulk and length of the chain increases.

Hansch equations put several of the parameters together to compare overall bioavailibility of different compounds.

Craig plots

Plots 2 constants

functional groups with similar activity will be in the same quadrant

the optimum quadrant, eg +ve σ and -ve π, will contain all the substituents worth investigating