Since Lipinski first published his "rule-of-five," drug discovery scientists have become more and more focused on the chemical properties of their compounds during the discovery process.  Furthermore, Wenlock and others have shown that the chemical properties associated with high attrition rates in the clinic further limit these properties, in particular molecular weight.

FBLD has provides a facile mechanism for identification of low molecular weight starting points during the early discovery phase.  Although the potency of these starting points can be very weak (~1mM), fragments with binding in the triple digit micromolar range are often identified and fragments of all starting potencies, even at the mM range, have been successfully optimized to nM leads.

 
In contrast to typical high-throughput screening libraries, fragment libraries at a minimum have a molecular weight cut-off of 300 and our libraries have a cut-off of 225 with an average molecular weight of ~150.  Since lead optimization has been shown to add ~100 in molecular weight, even starting with a 300 MW fragment is expected to yield at a minimum a 400 MW lead. 

Since our internal programs are targeted at CNS disease, we start with very small fragments so that our lead compounds will be in the range of 275-350.

Smaller starting points also require fewer compounds to cover diversity space.  Our libraries are focused on high core diversity and provide multiple unique starting points expected to yield a diverse portfolio of early leads each with a unique IP path. During fragment optimization, we closely monitor ligand efficiency and other chemical properties to remain within those most consistent with success in the clinic.

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