Lessons for fragment library design: analysis of output from multiple screening campaigns |
| |
Authors: | I-Jen Chen Roderick E Hubbard |
| |
Institution: | (1) Vernalis (R&D) Ltd, Granta Park, Cambridge, CB21 6GB, UK;(2) YSBL and HYMS, University of York, York, YO10 5YW, UK |
| |
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.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. |
| |
Keywords: | Fragment screening Fragment based drug discovery Library design Chemical space |
本文献已被 SpringerLink 等数据库收录! |
|