Experimental Validation of a Fragment Library for Lead Discovery Using SPR Biosensor Technology

Fragment - based Lead Discovery

Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery.

In fragment-based drug discovery, the weak affinities exhibited by fragments pose significant challenges for screening. Biophysical techniques are used to address this challenge, but there is no clear consensus on which cascade of methods is best suited to identify fragment hits that ultimately translate into bound X-ray structures and provide bona fide starting points for synthesis. We have be...

[Fragment screening using surface plasmon resonance optical biosensor technology].

A surface plasmon resonance (SPR) optical biosensor is a label-free biophysical device which can detect molecular interaction in real time. SPR is an emerging technology for fragment screening, the first step in fragment-based drug discovery. Low levels of protein consumption and the ability to detect interactions with K(d) as low as mM make this technology particularly attractive. Inherently s...

Fragment-based lead discovery using X-ray crystallography.

Fragment screening offers an alternative to traditional screening for discovering new leads in drug discovery programs. This paper describes a fragment screening methodology based on high throughput X-ray crystallography. The method is illustrated against five proteins (p38 MAP kinase, CDK2, thrombin, ribonuclease A, and PTP1B). The fragments identified have weak potency (>100 microM) but are e...

Fragment-Based Lead Discovery by NMR

fragment-based lead discovery because it combines high sensitivity and robustness to loose fragment binders with unique structural resolution and throughput. Favourable applications include screening against shallow binding pockets (such as protein-protein interactions) and side-pockets outside the highly conserved active centre of the major target classes (such as protein kinases and proteases...