Substituents of life: The most common substituent patterns present in natural products

Abstract

Comparison of substituents present in natural products with the substituents found in average synthetic molecules revealed considerable differences between these 2 groups. The natural products substituents contain mostly oxygen atoms and very little other heteroatoms, are structurally more complex, often containing double bonds and are rich in stereocenters. Substituents found in synthetic molecules contain nitrogen and sulfur atoms, halogenes and more aromatic and particularly heteroaromatic rings. The characteristics of substituents typical for natural products identified here can be useful in the medicinal chemistry context, for example to guide the synthesis of natural product-like libraries and natural product-inspired fragment collections. The results may be used also to support compound derivatization strategies and the design of pseudo-natural natural products.

Ring systems in natural products: structural diversity, physicochemical properties, and coverage by synthetic compounds

“…Rank 3 is held by 4 H -chromen-4-one, which is part of the flavone backbone. Cyclohexane and furan are ranked 5 and 6, respectively (cyclohexane is part of many sugar-like moieties and furan is known as the second most frequent ring in NP substituents 42 besides benzene). Beyond the most common ring systems, the frequencies of occurrence of the individual ring systems drop steeply (ESI Fig.…”

The Time and Place for Nature in Drug Discovery

“…Such methods are perhaps at odds with contemporary drug discovery practices, where practitioners remain heavily focused on a numbers-driven process through screening of molecules that can be made rapidly and cheaply, − contrasting to former practices of targeting designed natural product-like or biomimetic structures that often required more complex syntheses . The following discussion is not about natural products per se, a subject well-covered in recent reviews, − rather the contextualisation of the importance of the features and motifs inherent to physiological molecules and bioactive exogenous natural products is presented . This notion is developed to include variations on Nature’s themes through pseudo-natural products and the inherent opportunities presented through an increased employment of biotransformations in synthetic approaches toward bioactive molecules.…”

MORTAR - A Rich Client Application for in silico Molecule Fragmentation

“…A more sophisticated example study for the MORTAR pipelining functionality is inspired by the recent work of Peter Ertl to identify the most common substituents in natural products [47].…”

“…Figure 9 chemical space by which functional groups appear frequently in their structures, together with a comparison to non-natural product compounds [28], and analogous studies on structures relevant to medicinal chemistry [53]. Even more sophisticated analyses like the investigation of natural product substituents [47] can be attempted in a similar fashion using MORTAR's pipelining functionality. Looking at specific substructures and their frequencies in a structural database can also be used to access its chemical diversity.…”