Improved prediction of drug physicochemical properties

Supervisors: Dr. David Manallack and Dr. Richard Prankerd

Contact:
david.manallack@pharm.monash.edu.au  
David Manallack
Tel: 9903 9537
Department of Medicinal Chemistry
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University [Parkville Campus]

richard.prankerd@pharm.monash.edu.au
Richard Prankerd
Tel: 9903 9003
Department of Pharmaceutics
Faculty of Pharmacy and Pharmaceutical Sciences
Monash University [Parkville Campus]

Honours project for 2008

The present era of drug discovery is characterised by large libraries of potential lead compounds and high throughput screening for possible drug-like properties, hopefully leading to novel or improved pharmacological activity. The importance of fundamental drug physicochemical properties to this work is high. These properties include drug stability, acid-base behaviour, solubilities, partitioning and metabolic reactivities. At present, the available suitable ways for providing pKa values (acid dissociation constants) are through in silico computer estimations based solely on chemical structure and through experimental screening procedures such as capillary electrophoresis coupled to mass spectrometry. The first of these methods is still insufficiently accurate to give results that are absolutely reliable to much better than ±1 log unit, while the second, though somewhat more accurate, is significantly slower, and still not as accurate as desired. A pKa value in error by 1 log unit can result in solubilities and bioavailabilities that are 10-fold too low, or degradation rate constants that are 10-fold higher than expected. Part of the difficulty with pKa values (in common with other physicochemical quantities) is that these are free energy (ΔG) related terms made up of two other energy-related quantities, the changes in enthalpy (ΔH) and entropy (ΔS) for ionization. In many cases, the effects of enthalpy (ΔH) and entropy (ΔS) for ionization as a function of structure, lead to opposing effects on the free energy. Predictions of these quantities, based on structure, are few in number, but they have been shown to lead to relatively simple relationships in some cases.

The current project is intended to explore some of the possibilities of using enthalpy and entropy data for pKa prediction, in three parts:

(a) development of computer models for prediction of ΔH and ΔS from molecular structure, using a model set of data from the literature for over 60 carboxylic acids;
(b) measurement of ΔH for ionization for a range of drugs or drug-like compounds with known pKa values, and calculation of the corresponding values of ΔS for ionization from the Gibbs’ equation. Measurement of ΔH for ionization will use a direct isothermal titration microcalorimetric method;
(c) application of the methods developed in (a) to the new data from (b)

This project will result in measurement of novel, good quality data which is suitable for publication, and would particularly suit a student wishing to progress to PhD studies in this area. It offers the possibilities of performing sophisticated computer modelling in conjunction with precision measurement of physicochemical data using one of the very few microcalorimetry facilities in Australia.