Comprehensive analysis of commercial fragment libraries

Abstract

Screening of fragment libraries is a valuable approach to the drug discovery process. The quality of the library is one of the keys to success, and more particularly the design or choice of a library has to meet the specificities of the research program. In this study, we made an inventory of the commercial fragment libraries and we established a methodology which allows any library to be positioned in relation to the complete offer currently on the market, by addressing the following questions: does this chemical library look like another chemical library? What is the coverage of the current chemical space by this chemical library? What are the characteristic structural features of the fragments of this chemical library? We based our analysis on 2D and 3D chemical descriptors, framework class generation and the generative topographic map. We identified 59 270 scaffolds, which can be searched in a dedicated web site (https://gtmfrag.drugdesign.unistra.fr) and developed a model which accounts for fragment diversity while being easy to interpret (download at 10.5281/zenodo.5534434).