Fragment Based Drug Discovery is a new approach for Drug Discovery and Development by which fragment screening is performed to find new interesting fragments that can be developed into lead molecules. Recent research at Linnaeus University has been performed with the purpose to develop WACTM as a new technique for this particular application. WACTM represents an affordable, accessible and reliable fragment screening technique that requires standard HPLC equipment.
When new pharmaceuticals are developed, knowing which proteins/enzymes that are involved in the process causing the disease is essential. With this knowledge the pharmaceutical chemist tries to design a molecule that can regulate the activity
of the disease related proteins (target proteins), so that the symptoms of the illness are reduced or eliminated.
A relatively new way of developing pharmaceuticals is to use so called fragment based screening. This technology depends on having a library of many small molecules (fragments) that represent a broad selection of chemical structures. By
searching through (screening) the fragment-library for molecules that bind to a target protein one can find structures that then are combined or developed to drug candidates.
Due to their modest size, the fragments often bind with low affinity with KD values in the mM-µM range. It is therefore necessary to use methods that are sensitive enough to detect these weak bonds between the fragment molecule and the target
proteins during fragment screening. It is common to use a combination of techniques to find useful fragments. New fragment screening methods that can complement the existing ones are of great interest.
The objective of Dr Minh-Dao Duong-Thi’s and Dr Elinor Meiby’s recently published doctoral dissertations at the Linnaeus University in Kalmar was to introduce the technology Weak Affinity Chromatography (WAC) in Drug Discovery and Development
for fragment screening and assessment of progressive fragments.
WAC is a method based on HPLC where the target protein is immobilized onto the support material of a column. While passing through the column, the molecules that do not bind to the target protein in the column pass quickly through the column
while the molecules that bind to it will be delayed. From this delay the affinity (kD) can be determined. This technology has considerable advantages; it is fast and robust, it can be performed on mixtures of molecules such as stereoisomers
and one can get information about affinity from a single sample of the analyte even with very weak binding in the mM range.
Minh-Dao’s complete doctoral dissertation.
Elinor’s complete disertation.
Open access article: Fragment Screening of cyclin G-associated kinase by weak affinity chromatography.