Drug interactions with lipid membranes: the effects of drug and lipid structure upon rates of ester hydrolysis
Author(s)
Casey, Duncan Robert
Type
Thesis
Abstract
The transport of compounds around the body has been a topic of interest for many years, and the advent of non-invasive biological imaging in living tissue has made huge advances in the characterisation and localisation of cellular receptors for use in drug targeting. However, there remains a significant paucity of knowledge regarding how the majority of drug molecules are transported about the body, when they often exhibit negligible aqueous solubility and the body expresses no trans-membrane pumps or chaperone proteins that recognise them and facilitate their movement. This leads to large attrition rates in drug discovery programmes, as compounds with high binding constants or inhibitive activity in vitro fail to perform in vivo, due to poor bioavailability or non-specific sequestration away from the tissue of interest.
In this study, the interactions between a number of drug and lipid molecules were investigated and the effects upon both the lipids’ chemical and bulk membrane structures were analysed. This revealed some of the mechanistic causes of the previously observed hydrolytic activity a number of common drug compounds exhibit toward lipid membranes and identified parameters affecting the observed rates of reaction. The findings also suggest approaches by which this behaviour might be predicted, or even tuned to deliver optimum pharmacological characteristics.
In this study, the interactions between a number of drug and lipid molecules were investigated and the effects upon both the lipids’ chemical and bulk membrane structures were analysed. This revealed some of the mechanistic causes of the previously observed hydrolytic activity a number of common drug compounds exhibit toward lipid membranes and identified parameters affecting the observed rates of reaction. The findings also suggest approaches by which this behaviour might be predicted, or even tuned to deliver optimum pharmacological characteristics.
Date Issued
2011-06
Date Awarded
2012-01
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Templer, Richard
Long, Nicholas
Law, Robert
Ces, Oscar
Creator
Casey, Duncan Robert
Publisher Department
Chemistry
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)