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From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design
Author(s) -
Friedrich Lukas,
Rodrigues Tiago,
Neuhaus Claudia S.,
Schneider Petra,
Schneider Gisbert
Publication year - 2016
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201601941
Subject(s) - natural product , combinatorial chemistry , chemistry , affinities , biochemical engineering , binding affinities , simple (philosophy) , computer science , stereochemistry , biochemistry , engineering , receptor , philosophy , epistemology
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.