March 12, 2003

QUANTITATIVESTRUCTURE - ACTIVITY

RELATIONSHIP(QSAR)

INTRODUCTION

Quantitative Structure-Activity Relationship (QSAR) involve the derivation of a mathematical formula which relates the biological activities of a group of compounds to their physicochemical properties

Traditional QSAR is carried out on a range of analogs sharing a common skeleton, but having different substituents

PROCEDURE

An initial QSAR equation is derived relating biological activity to one or two physical features.The equation can then evolve by introducing other physical featuresThree physical features are of particular important : HYDROPHOBICITY, ELECTRONIC FACTOR, and STERIC FACTORS

HYDROPHOBICITY OF THE MOLECULE

The hydrophobicity of a molecule is measured by its logP value, where P is the partition coeficient.

The partition coeficient is the relative solubility of the compound in octanol and water

Substituent Hydrophobicity Constant

The hydrophobic character of a substituent is given by substituent hydrophobicity constant (π)

π values can be used to calculate logP values and can be introduced into QSAR equations to determine wheter hydrophobicity substituents at specific regions of a structure are important to activity

Electronic properties

The electronic properties of aromatic substituents are measured as Hammett substituent cinstant (σ)

Substituent with positive σ values are electron withdrawing, whereas substituents with negative σ values are electron donating

The steric Factor

Taft’s steric factor (Es) is measured experimentally

Molar refractivity (MR) is a measure of size calculated from substituent’s molecular weight, index of refraction, and density

Verloop steric parameters are calculated by a computer software program

HANSCH Equation

The Hansch equation is the name given to QSAR equation and typically contains physical factor such as logP, π, σ, F, R, Es, and MR

The substituents used to derive a Hansch equation must present a good spread of values for each physical parameter and also distinguish between the parameter

CRAIG Plots

Craig plots compare two physical properties for different substituents.

They are used to identify which substituents are valid for derivation of a Hansch equation including these properties

Other factors

Other physicochemical factors such as dipole moments, basicity, and the presence of specific substituents may be included in QSAR equations

TOPLISS Schemes

Topliss schemes are used when compounds are synthesized and tested one at the time.

The scheme is used to decide which analog to synthesize nuxt, based on the activity of the previous compounda and possible effect of a substituent’s hydrophobic, electronic, and steric properties

Three – Dimensional QSAR

Three – dimensional QSAR involves the calculation of steric and electronic fields around molecules.Three – dimensional QSAR is not restricted to compounds having the same skeleton and can be used for molecules sharing a common pharmacophore, or which bind to the same binding siteThe effect of steric and electronic fields on activity can be shown visually by contour map