Natural products
are the result of Nature’s exploration
of biologically relevant chemical space through evolution and an invaluable
source of bioactive small molecules for chemical biology and medicinal
chemistry. Novel concepts for the discovery of new bioactive compound
classes based on natural product structure may enable exploration
of wider biologically relevant chemical space. The pseudo-natural
product concept merges the relevance of natural product structure
with efficient exploration of chemical space by means of fragment-based
compound development to inspire the discovery of new bioactive chemical
matter through
de novo
combination of natural product
fragments in unprecedented arrangements. The novel scaffolds retain
the biological relevance of natural products but are not obtainable
through known biosynthetic pathways which can lead to new chemotypes
that may have unexpected or unprecedented bioactivities. Herein, we
cover the workflow of pseudo-natural product design and development,
highlight recent examples, and discuss a cheminformatic analysis in
which a significant portion of biologically active synthetic compounds
were found to be pseudo-natural products. We compare the concept to
natural evolution and discuss pseudo-natural products as the human-made
equivalent, i.e. the chemical evolution of natural product structure.
Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.
A method is described that demonstrates a new technique for rapid and high‐throughput single molecule sequencing. This sequencing technique is based on the successive enzymatic degradation of fluorescently labeled single DNA molecules, and the detection and identification of the released monomer molecules according to their sequential order in a microstructured channel.
The detection technique is evolved from confocal fluorescence microscopy, with two different laser sources to excite the individual mononucleotides that are either labeled with tetramethylrhodamine (TMR) or Cyanine5 (Cy5). The handling of DNA which is immobilized on carrier beads, and the detection of the cleaved monomers is performed in optically transparent and biochemically inert microstructures (glass or PMMA) with detection channels of 7 μ × 10 μm.
The projected rate of sequencing is ≈100 bases min−1, dependent solely on the rate of the enzymatic DNA cleavage.
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