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Computational Macrocyclization: From de?novo Macrocycle Generation to Binding Affinity Estimation.

ABSTRACT: 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 de?novo macrocyclization, our results suggest that we have a robust protocol in hand to design macrocycles and prioritize them prior to synthesis.

SUBMITTER: Wagner V

PROVIDER: S-EPMC5725703 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Computational Macrocyclization: From de novo Macrocycle Generation to Binding Affinity Estimation.

Wagner Vincent V Jantz Linda L Briem Hans H Sommer Kai K Rarey Matthias M Christ Clara D CD

ChemMedChem 20171025 22

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 ...[more]

PMID: 28977738

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