Computational Macrocyclization: From denovo Macrocycle Generation to Binding Affinity Estimation

Macrocycles play an increasing role in drug discovery, but their synthesis is often demanding. Computational tools that suggest macrocyclization based on a known binding mode and that estimate the binding affinity of these macrocycles could have a substantial impact on the medicinal chemistry design...

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Bibliographic Details
Published in:ChemMedChem 2017-11, Vol.12 (22), p.1866
Main Authors: Wagner, Vincent, Jantz, Linda, Briem, Hans, Sommer, Kai, Rarey, Matthias, Christ, Clara D
Format: Article
Language:English
Subjects:
Affinity
Binding
Computation
Computer applications
Drug discovery
Software
Synthesis
Workflow
Online Access:Get full text
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Summary:Macrocycles play an increasing role in drug discovery, but their synthesis is often demanding. Computational tools that suggest macrocyclization based on a known binding mode and that estimate the binding affinity of these macrocycles could have a substantial impact on the medicinal chemistry design process. For both tasks, we established a workflow with high practical value. For five diverse pharmaceutical targets we show that the effect of macrocyclization on binding can be calculated robustly and accurately. Applying this method to macrocycles designed by LigMac, a search tool for denovo macrocyclization, our results suggest that we have a robust protocol in hand to design macrocycles and prioritize them prior to synthesis.
ISSN:1860-7179
1860-7187
DOI:10.1002/cmdc.201700478