Novel Chemical Space Exploration via Natural Products

Abstract

Natural products (NPs) are a rich source of novel compound classes and new drugs. In the present study we have used the chemical space navigation tool ChemGPS-NP to evaluate the chemical space occupancy by NPs and bioactive medicinal chemistry compounds from the database WOMBAT. The two sets differ notable in coverage of chemical space, and tangible lead-like NPs were found to cover regions of chemical space that lack representation in WOMBAT. Property based similarity calculations were performed to identify NP neighbours of approved drugs. Several of the NPs revealed by this method, were confirmed to exhibit the same activity as their drug neighbours. The identification of leads from a NP starting point may prove a useful strategy for drug discovery, in the search for novel leads with unique properties.

The re-emergence of natural products for drug discovery in the genomics era

“…To a certain extent, compound libraries are being designed to mimic more closely the chemical properties of natural products, 10,[13][14][15][16][17] although natural products themselves are generally overlooked.…”

“…Besides natural-product-likeness based on chemical structure, similarity measures can also be based on physicochemical properties 16 . The chemical space navigation tool ChemGPS-NP was used to analyse natural products and bioactive medicinal chemistry compounds in the WOMBAT database 16 .…”

“…The chemical space navigation tool ChemGPS-NP was used to analyse natural products and bioactive medicinal chemistry compounds in the WOMBAT database 16 . The overlap between the biologically relevant chemical space that was covered by natural products and the biologically relevant chemical space that was covered by medicinal chemistry compounds, was limited, showing that natural products cover parts of chemical space that lack representation by medicinal chemistry compounds.…”

“…The overlap between the biologically relevant chemical space that was covered by natural products and the biologically relevant chemical space that was covered by medicinal chemistry compounds, was limited, showing that natural products cover parts of chemical space that lack representation by medicinal chemistry compounds. Such natural products may be useful novel leads 16 . A comparison of the Euclidean distances (EDs) in chemical space between approved drugs included in the GVK BIO drug database and natural products from the Dictionary of Natural Products identified many drug natural-product pairs.…”

Visualisation of the chemical space of fragments, lead-like and drug-like molecules in PubChem

“…Among the various approaches reported sofar to represent chemical space [14][15][16], MQN-space has the advantage of simplicity. For instance chemical spaces have been constructed by assigning dimensions to descriptors such as eigenvalues of matrices constructed from primary descriptors [13,17,18], or more directly to descriptors of molecular structure and calculated physicochemical properties [19,20], or by using various types of fingerprints [21]. These descriptor sets are obtained from the molecular structures through complex and partly machine-controlled calculations, which renders the immediate understanding of the resulting chemical space inaccessible to non-specialists.…”