A new methodology for classifying fragment combinations and characterizing pseudo-natural products (PNPs) is described. The source code is based on open-source tools and is organized as a Python package. Tasks can be executed individually or within the context of scalable, robust workflows. First, structures are standardized and duplicate entries are filtered out. Then, molecules are probed for the presence of predefined fragments. For molecules with more than one match, fragment combinations are classified. The algorithm considers the pair-wise relative position of fragments within the molecule (fused atoms, linkers, intermediary rings), resulting in 18 different possible fragment combination categories. Finally, all combinations for a given molecule are assembled into a fragment combination graph, with fragments as nodes and combination types as edges. This workflow was applied to characterize PNPs in the ChEMBL database via comparison of fragment combination graphs with Natural Product (NP) references, represented by the Dictionary of Natural Products. The Murcko fragments extracted from 2,000 structures previously described were used to define NP-fragments. The results indicate that ca. 23% of the biologically relevant compounds listed in ChEMBL comply to the PNP definition, and that, therefore, PNPs occur frequently among known biologically relevant small molecules. The majority (>95%) of PNPs contains two to four fragments, mainly (>95%) distributed in five different combination types. These findings may provide guidance for the design of new PNPs.
Pseudo-Natural Products Occur Frequently in Biologically Relevant Compounds
27 July 2021, Version 1
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