Lessons for fragment library design: analysis of output from multiple screening campaigns

Abstract

Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets. Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening. We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we discuss how the results could inform further development and improvement of our fragment library.

Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics

“…In consideration of results for the 13 NMR-STD screens, only *33% of the total GFI-I collection hit at least one target, consistent with other studies [62].…”

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

“…This hit rate includes both true and false hits. A low hit rate does not reflect a limitation of the technique, but rather the potential druggability and stability of the target being investigated (42) or even the design of the library used (43).…”

Design Principles for Fragment Libraries: Maximizing the Value of Learnings from Pharma Fragment-Based Drug Discovery (FBDD) Programs for Use in Academia

“…71,72,73,74 It was also found that less polar fragments tend to bind with lower affinity and more promiscuously. 29,56,75 It seems that the presence of a strong hydrogen bond in the initial fragment indicates that a strong anchor point is likely to be maintained. 64 If the fragment does shift, it likely had multiple orientations in the first place, possibly disguised in poorly defined electron density.…”