caa a22 4500 52878675X 20190715031132.0 cr unu---uuuuu 180924e20180808xx s 000 0 eng 10.3929/ethz-b-000290645 doi 10.1038/s42004-018-0043-x doi (ETHRESEARCH)oai:www.research-collection.ethz.ch:20.500.11850/290645 Scaffold hopping from natural products to synthetic mimetics by holistic molecular similarity [Elektronische Daten] [Francesca Grisoni, Daniel Merk, Viviana Consonni, Jan Alexander; id_orcid 0000-0003-0559-4330 Hiss, Sara Giani Tagliabue, Roberto Todeschini, Gisbert; id_orcid 0000-0001-6706-1084 Schneider] Open access ethresearch 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. Creative Commons Attribution 4.0 International http://creativecommons.org/licenses/by/4.0 ethresearch Grisoni Francesca joint author Merk Daniel joint author Consonni Viviana joint author Hiss Jan Alexander; id_orcid 0000-0003-0559-4330 joint author Tagliabue Sara Giani joint author Todeschini Roberto joint author Schneider Gisbert; id_orcid 0000-0001-6706-1084 joint author Communications Chemistry London : Macmillan Publishers 1 (1), p. 44 http://hdl.handle.net/20.500.11850/290645 text/html WWW-Backlink auf das Repository (Open access) 1 Journal Article ethresearch ETHRESEARCH 856 40 http://hdl.handle.net/20.500.11850/290645 text/html WWW-Backlink auf das Repository (Open access) ETHRESEARCH 700 1- Grisoni Francesca joint author ETHRESEARCH 700 1- Merk Daniel joint author ETHRESEARCH 700 1- Consonni Viviana joint author ETHRESEARCH 700 1- Hiss Jan Alexander; id_orcid 0000-0003-0559-4330 joint author ETHRESEARCH 700 1- Tagliabue Sara Giani joint author ETHRESEARCH 700 1- Todeschini Roberto joint author ETHRESEARCH 700 1- Schneider Gisbert; id_orcid 0000-0001-6706-1084 joint author ETHRESEARCH 773 0- Communications Chemistry London : Macmillan Publishers 1 (1), p. 44 BK010053 XK010053 XK010000 ETHRESEARCH ETHRESEARCH ETHRESEARCH Journal Article Open access