We report a comprehensive fragment library with 205,903 fragments derived from the recently published Collection of Open Natural Products (COCONUT) data set with more than 400,000 non‐redundant natural products. The natural products‐based fragment library was compared with other two fragment libraries herein generated from ChEMBL (biologically relevant compounds) and Enamine‐REAL (a large on‐demand collection of synthetic compounds), both used as reference data sets with relevance in drug discovery. It was found that there is a large diversity of unique fragments derived from natural products and that the entire structures and fragments derived from natural products are more diverse and structurally complex than the two reference compound collections. During this work we introduced a novel visual representation of the chemical space based on the recently published concept of statistical‐based database fingerprint. The compounds and fragments libraries from natural products generated and analyzed in this work are freely available.

Natural products and semi-synthetic compounds continue to be a significant source of drug candidates for a broad range of diseases, including coronavirus disease 2019 (COVID-19), which is causing the current pandemic. Besides being attractive sources of bioactive compounds for further development or optimization, natural products are excellent substrates of unique substructures for fragment-based drug discovery. To this end, fragment libraries should be incorporated into automated drug design pipelines. However, public fragment libraries based on extensive collections of natural products are still limited. Herein, we report the generation and analysis of a fragment library of natural products derived from a database with more than 400,000 compounds. We also report fragment libraries of a large food chemical database and other compound datasets of interest in drug discovery, including compound libraries relevant for COVID-19 drug discovery. The fragment libraries were characterized in terms of content and diversity.

Technological advances and practical applications of the chemical space concept in drug discovery, natural product research, and other research areas have attracted the scientific community´s attention. The large-and ultra-large chemical spaces are associated not only with the significant increase in the number of compounds that can potentially be made and exist but also with the increasing number of experimental and calculated descriptors that are emerging that encode the molecular structure and/or property aspects of the molecules. Due to the importance and continued evolution of compound libraries, herein, we discuss definitions proposed in the literature for chemical space. We also introduce the concept of chemical multiverse as an alternative view of the chemical space and discuss it considering a related idea: consensus chemical space.

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