Identification and Selection of “Privileged Fragments” Suitable for Primary Screening

The use of small molecule libraries for fragment-based primary screening (FBS) is a well-known approach to identify protein binders in the low affinity range. However, the search, analysis, and selection of suitable screening fragments can be a lengthy process, because of the large number of compounds that must be analyzed for different levels of ring/substituents identification and submitted to selection/exclusion criteria based on their physicochemical properties. The purpose of the present work is to propose a strategy to identify substructures from databases of known drugs, which can be used as templates for the generation of libraries of “privileged fragments” that are able to provide high-quality hits. The entire process has been developed integrating Pipeline Pilot (Accelrys Inc., San Diego, CA; http://www.accelrys.com) native components and user-defined molecular files containing ISIS-like substructure query features (Symyx, San Ramon, CA; http://www.symyx.com). The method is effortless, easy to put in place, and fast enough to be iteratively applied to different sources of druglike compounds.