Scaffold hopping from natural products to synthetic mimetics by holistic molecular similarity
Abstract
Natural products offer unexplored molecular frameworks for the development of chemical leads and innovative drugs. However, the structural complexity of natural products compared with synthetic drug-like molecules often limits the scaffold hopping potential of natural-product-inspired molecular design. Here we introduce a holistic molecular representation incorporating pharmacophore and shape patterns, which facilitates scaffold hopping from natural products to isofunctional synthetic compounds. This computational approach captures simultaneously the partial charge, atom distributions and molecular shape. In a prospective application, we use four natural cannabinoids as queries in a chemical database search for novel synthetic modulators of human cannabinoid receptors. Of the synthetic compounds selected by the new method, 35% are experimentally confirmed as active. These cannabinoid receptor modulators are structurally less complex than their respective natural product templates. The results of this study validate this holistic molecular representation for hit and lead finding in drug discovery. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000290645Publication status
publishedExternal links
Journal / series
Communications ChemistryVolume
Pages / Article No.
Publisher
Macmillan PublishersOrganisational unit
03852 - Schneider, Gisbert / Schneider, Gisbert
Funding
177477 - Beyond fragment-based drug design: from natural products to small synthetic mimetics through novel holistic molecular representations (SNF)
More
Show all metadata
ETH Bibliography
yes
Altmetrics