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 predicte...

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Published inAngewandte 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
LanguageEnglish
Published WEINHEIM Blackwell Publishing Ltd 01.06.2016
Wiley
Wiley Subscription Services, Inc
EditionInternational 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
Online AccessGet full text

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Abstract 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.
AbstractList 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.
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.
We present the computational denovo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (-)-EnglerinA. 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 (-)-EnglerinA 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.
Abstract 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.
Author Schneider, Gisbert
Rodrigues, Tiago
Friedrich, Lukas
Schneider, Petra
Neuhaus, Claudia S.
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Keywords MACROMOLECULAR TARGETS
MOLECULAR SIMILARITY
LIBRARIES
chemical biology
computer-assisted drug design
drug discovery
LIGANDS
organic synthesis
polypharmacology
BIOLOGY
CHEMISTRY
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TRPM8
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Snippet We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (−)‐Englerin A....
We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (-)-Englerin A....
We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (-)-Englerin A....
Abstract We present the computational de novo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product...
We present the computational denovo design of synthetically accessible chemical entities that mimic the complex sesquiterpene natural product (-)-EnglerinA. We...
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SubjectTerms 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
Title From Complex Natural Products to Simple Synthetic Mimetics by Computational De Novo Design
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https://search.proquest.com/docview/1792376065
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