From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design.
We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (-)-Englerin A. We synthesized lead-like probes from commercially available building blocks and profiled them for activity against a computationally predicted panel of macromolecular targets. Both the design template (-)-Englerin A and its low-molecular weight mimetics presented nanomolar binding affinities and antagonized the transient receptor potential calcium channel TRPM8 in a cell-based assay, without showing target promiscuity or frequent-hitter properties. This proof-of-concept study outlines an expeditious solution to obtaining natural-product-inspired chemical matter with desirable properties.
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Lukas
L
Friedrich
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Tiago
T
Rodrigues
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.
Claudia S
CS
Neuhaus
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland.|inSili.com GmbH, Segantinisteig 3, 8049, Zurich, Switzerland.
Petra
P
Schneider
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH), Vladimir-Prelog-Weg 4, 8093, Zurich, Switzerland. gisbert.schneider@pharma.ethz.ch.
Gisbert
G
Schneider
chemical biology; computer-assisted drug design; drug discovery; organic synthesis; polypharmacology