From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design

• Published in: Angewandte Chemie International Edition Vol. 55; no. 23; pp. 6789 - 6792
• Main Authors: Friedrich, Lukas, Rodrigues, Tiago, Neuhaus, Claudia S., Schneider, Petra, Schneider, Gisbert
• Format: Journal Article
• Language: English
• Published: WEINHEIM Blackwell Publishing Ltd 01.06.2016; Wiley; Wiley Subscription Services, Inc
• Edition: International ed. in English
• Subjects: Accessibility; Assaying; Binding; Calcium; chemical biology; Chemistry; Chemistry, Multidisciplinary; Computer applications; computer-assisted drug design; Design; drug discovery; Lead; Macromolecules; Molecular weight; Nanostructure; Natural products; organic synthesis; Physical Sciences; polypharmacology; Probes; Science & Technology; Transient receptor potential proteins; MACROMOLECULAR TARGETS; MOLECULAR SIMILARITY; LIBRARIES; chemical biology; computer-assisted drug design; drug discovery; LIGANDS; organic synthesis; polypharmacology; BIOLOGY; CHEMISTRY; CHEMICAL SPACE; TRPM8; SCAFFOLD
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201601941

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. Natural‐product‐inspired synthesis: Computer‐based molecular design suggested synthetically accessible, low molecular weight compounds as mimetics of a complex natural product. The template Englerin A and the designed compounds potently block TRPM8 channels, showing how computational design can be used to generate natural‐product‐inspired tool compounds for chemical biology and drug discovery.