Abstract
Natural products are universally recognized to contribute valuable chemical diversity to the design of molecular screening libraries. The analysis undertaken in this work, provides a foundation for the generation of fragment screening libraries that capture the diverse range of molecular recognition building blocks embedded within natural products. Physicochemical properties were used to select fragment-sized natural products from a database of known natural products (Dictionary of Natural Products). PCA analysis was used to illustrate the positioning of the fragment subset within the property space of the non-fragment sized natural products in the dataset. Structural diversity was analysed by three distinct methods: atom function analysis, using pharmacophore fingerprints, atom type analysis, using radial fingerprints, and scaffold analysis. Small pharmacophore triplets, representing the range of chemical features present in natural products that are capable of engaging in molecular interactions with small, contiguous areas of protein binding surfaces, were analysed. We demonstrate that fragment-sized natural products capture more than half of the small pharmacophore triplet diversity observed in non fragment-sized natural product datasets. Atom type analysis using radial fingerprints was represented by a self-organizing map. We examined the structural diversity of non-flat fragment-sized natural product scaffolds, rich in sp3 configured centres. From these results we demonstrate that 2-ring fragment-sized natural products effectively balance the opposing characteristics of minimal complexity and broad structural diversity when compared to the larger, more complex fragment-like natural products. These naturally-derived fragments could be used as the starting point for the generation of a highly diverse library with the scope for further medicinal chemistry elaboration due to their minimal structural complexity. This study highlights the possibility to capture a high proportion of the individual molecular interaction motifs embedded within natural products using a fragment screening library spanning 422 structural clusters and comprised of approximately 2800 natural products.
Highlights
Natural products (NPs) have played a pivotal role in the discovery and development of therapeutic drugs.[1]
The composition of the database is a reflection of numerous biases related to the collection, isolation or identification of biota and their chemical constituents, the Dictionary of Natural Products (DNP) is regarded as a good representative collection of all known natural products
Fragment-like structures were identified by the empirical rule of three Ro3 in which molecular weight (MW) is < 300 Da, ClogP is 3, hydrogen bond donors (HBD) is 3 and hydrogen bond acceptors (HBA) is 3.[14]. Later, experimental evidence suggested a lower molecular weight cutoff would be more appropriate in fragment screening collections.[15]
Summary
Natural products (NPs) have played a pivotal role in the discovery and development of therapeutic drugs.[1]. Biodiversity medicine for thousands of years and according to the World Health Organisation (WHO) are still relied upon for primary health care by approximately 80% of the residents of developing countries.[2] Investigation of structural differences between natural products, drug substances and other chemicals, found that natural products interrogate a different and wider chemical space than synthetic derivatives.[3,4,5,6] it has been showed that 83% of core ring scaffolds (12977) present in NPs were absent from commercially available molecules and screening libraries.[7] The authors suggested that including molecules containing scaffolds present in natural products would provide better opportunities to find both screening hits and chemical biology probes.[7] creating a high quality library incorporating unique natural product scaffolds would present a synthetic challenge due to the enormous number of scaffolds.[8] This challenge becomes less if fragment-based drug discovery (FBDD) is considered. In contrast to normal screening libraries, FBDD screens smaller libraries of relatively simple compounds with low-range molecular weight (150–300 Da).[9, 10] The exploitation of fragment combinatorics leads to greater coverage of chemical space.[11]
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