Abstract
Natural Products (NPs) are molecular' special equipment ' that impart survival benefits on their producers in nature. Due to their evolved functions to modulate biology these privileged metabolites are substantially represented in the drug market and are continuing to contribute to the discovery of innovative medicines such as the recently approved semi-synthetic derivative of the bacterial alkaloid staurosporin in oncology indications. The innovation of low molecular weight compounds in modern drug discovery is built on rapid progress in chemical, molecular biological, pharmacological and data sciences, which together provide a rich understanding of disease-driving molecular interactions and how to modulate them. NPs investigated in these pharmaceutical research areas create new perspectives on their chemical and biological features and thereby new chances to advance medical research. New methods in analytical chemistry linked with searchable NP-databases solved the issue of reisolation and enabled targeted and efficient access to novel molecules from nature. Cheminformatics delivers high resolution descriptions of NPs and explores the substructures that systematically map NP-chemical space by sp³-enriched fragments. Whole genome sequencing has revealed the existence of collocated gene clusters that form larger functional entities together with proximate resistance factors thus avoiding self-inhibition of the encoded metabolites. The analysis of bacterial and fungal genes provides tantalizing glimpses of new compound-target pairs of therapeutic value. Furthermore, a dedicated investigation of structurally unique, selectively active NPs in chemical biology demonstrates their extraordinary power as shuttles between new biological target spaces of pharmaceutical relevance.
Highlights
Natural products (NPs) interact with, and regulate, a plethora of physiological pathways in nature
In contrast to ‘primary metabolites’ which are essential for living cells, these ‘secondary metabolites’ are not survival-critical, they do represent chemical ‘special equipment’ for plants, microorganisms, and animals conveying survival advantages in their biological habitats.[1a–f] Due to their evolutionary relatedness, these ‘fitness factors’ can modulate the activity of their target homologs and paralogs in higher animals.[2a–e] The biological functions of NPs make them a valuable source of chemical probes for discovering novel molecular interactions at the heart of diverse human diseases
Natural Product Fragments Fragment-based drug discovery (FBDD) has matured into a well-established and widely used technology that reliably delivers relevant chemical starting points for therapeutic drug projects, and which complements the outcome of more traditional hit finding strategies like high-throughput screening of large compound libraries.[24]
Summary
Natural products (NPs) interact with, and regulate, a plethora of physiological pathways in nature.
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