QSAR - Quantitative Structure-Activity Relationships PDF

Quantitative Structure-Activity Relationships (QSAR) Patrick Chapter 18 Can one derive an equation that quantifies the relationship between calculated properties and biological activity that will allow one to predict the biological activity to some extent? Goal is to find best compound in the most e...

Quantitative Structure-Activity Relationships (QSAR) Patrick Chapter 18 Can one derive an equation that quantifies the relationship between calculated properties and biological activity that will allow one to predict the biological activity to some extent? Goal is to find best compound in the most efficient manner possible. QSAR: Relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula Requires: Quantitative measurements for biological and physicochemical properties Physicochemical Properties 1. Hydrophobicity of the molecule 2. Hydrophobicity of substituents 3. Electronic properties of substituents 4. Steric properties of substituents Most common properties studied 1. Hydrophobicity of the Molecule in octanol] Partition Coefficient P = [Drug [Drug in water] High P High hydrophobicity Activity of drugs is often related to P e.g. binding of drugs to serum albumin (straight line - limited range of log P) Log (1/C)......... 0.78 3.82 1  Log  C 0.75 logP + 2.30 Log P Binding increases as log P increases Binding is greater for hydrophobic drugs C = concentration of drug required to achieve a defined level of biological activity (e.g., IC 50) Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Log (1/C) 1  2 Log  C - 0.22(logP) + 1.04 logP + 2.16 o Log P Log P Optimum value of log P for anaesthetic activity = log Po QSAR equations are only applicable to compounds in the same structural class (e.g. ethers) However, log Po is similar for anaesthetics of different structural classes (ca. 2.3) Structures with log P ca. 2.3 enter the CNS easily (e.g. potent barbiturates have a log P of approximately 2.0) Can alter log P value of drugs away from 2.0 to avoid CNS side effects