Fragment-based drug design (FBDD) has emerged as a powerful screening technology for the identification of small molecules that bind weakly but efficiently to biological targets. FBDD has already been successfully applied to a large set of protein targets (a, b) but a series of challenges remain to be overcome especially in the design of new chemical libraries. This is indeed considered as a pivotal element in fragment-based lead discovery, because even if small fragment libraries (between 1000 and 10 000 compounds) are considered large enough to probe chemical space efficiently, many fragment libraries contain essentially planar aromatic scaffolds. This lack of 3-D diversity(c) might limit the success rate for a certain class of targets. Our first goal was to improve the chemical diversity of our in-house fragment library while matching synthetically accessible 3-D chemical space with biological target space. For that purpose we first developed a microwave assisted synthesis of spirohydantoins enriched in sp3 carbon atoms. We then developed chemical pathways to introduce the diversity around these new templates in the three dimension of the chemical space. Finally, a virtual library of elaborated spirohydantoins was synthesized in silico using commercially available alkylating agents. As expected, these new compounds are able to fully cover the chemical space. In-silico screening of this library will help us to identify biological active compounds.

Highly functionalized spirohydantoins as 3-dimensional templates for fragment screening

251st National Meeting (2016)

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