Classifying shape coverage in fragment libraries using a fingerprinting approach

Fragment screening is one approach to hit identification for early stage drug discovery projects. Like any screening library, diversity is needed in fragment libraries. This includes coverage of shape and electrostatic space, as well as chemotype diversity. A new, easily interpretable shape-based fingerprint is described and its utility in probing fragment library content is demonstrated using a Rule of Three library from Maybridge. This method explicitly considers size as a component of shape. It allows interrogation of shape space on both a per conformer and a per molecule level, and includes a measure of flexibility. This allows for the identification of highly flexible compounds and their exclusion from the analysis. A comparison with two literature methods, the triangle plot approach of Sauer and Schwarz and the plane of best fit method of Firth et al., is also included.