The recent success
of fragment-based drug discovery (FBDD) is inextricably
linked to adequate library design. To guide the design of our fragment
libraries, we have constructed an automated workflow in the open-source
KNIME software. The workflow considers chemical diversity and novelty
of the fragments, and can also take into account the three-dimensional
(3D) character. This design tool can be used to create large and diverse
libraries but also to select a small number of representative compounds
as a focused set of unique screening compounds to enrich existing
fragment libraries. To illustrate the procedures, the design and synthesis
of a 10-membered focused library is reported based on the cyclopropane
scaffold, which is underrepresented in our existing fragment screening
library. Analysis of the focused compound set indicates significant
shape diversity and a favorable overall physicochemical profile. By
virtue of its modular setup, the workflow can be readily adjusted
to design libraries that focus on properties other than 3D shape.