ArticleJournal of the American Chemical Society2017
Structure-Activity Relationship and Molecular Mechanics Reveal the Importance of Ring Entropy in the Biosynthesis and Activity of a Natural Product.
Article in Journal of the American Chemical Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
26 citing papers in PubMed, 51 citations in OpenAlex.
- A Framework for the In Vivo Production of Extensively Engineered Thiopeptides.ACS synthetic biology · 2026Article
- NPCDR 2.0: the activity and structure landscape of natural product-based drug combination.Nucleic acids research · 2026Article
- Robust Conformational Space Exploration of Cyclic Peptides by Combining Different MD Protocols and Force Fields.Journal of chemical theory and computation · 2025Article
- De novo design of ribosomally synthesized and post-translationally modified peptides.Nature chemistry · 2025Article
- Late-Stage Reshaping of Phage-Displayed Libraries to Macrocyclic and Bicyclic Landscapes using a Multipurpose Linchpin.Journal of the American Chemical Society · 2025Article
- Use of a head-to-tail peptide cyclase to prepare hybrid RiPPs.Chemical communications (Cambridge, England) · 2024Article
- A Compact Reprogrammed Genetic Code for De Novo Discovery of Proteolytically Stable Thiopeptides.Journal of the American Chemical Society · 2024Article
- Deep Learning-Driven Library Design for theACS central science · 2023Article
- De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors.Journal of the American Chemical Society · 2022Article
- Accurate Models of Substrate Preferences of Post-Translational Modification Enzymes from a Combination of mRNA Display and Deep Learning.ACS central science · 2022Article
- Chirality-matched catalyst-controlled macrocyclization reactions.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Genetically-encoded discovery of proteolytically stable bicyclic inhibitors for morphogen NODAL.Chemical science · 2021Article
- New developments in RiPP discovery, enzymology and engineering.Natural product reports · 2021Review
- Thiopeptides Induce Proteasome-Independent Activation of Cellular Mitophagy.ACS chemical biology · 2020Article
- Interception of the Bycroft-Gowland Intermediate in the Enzymatic Macrocyclization of Thiopeptides.Journal of the American Chemical Society · 2020Article
- Minimal lactazole scaffold for in vitro thiopeptide bioengineering.Nature communications · 2020Article
- Crossroads of Antibiotic Resistance and Biosynthesis.Journal of molecular biology · 2019Review
- Dehydroamino acids: chemical multi-tools for late-stage diversification.Organic & biomolecular chemistry · 2019Review
- Thiopeptide Pyridine Synthase TbtD Catalyzes an Intermolecular Formal Aza-Diels-Alder Reaction.Journal of the American Chemical Society · 2019Article
- Flexizyme-Enabled Benchtop Biosynthesis of Thiopeptides.Journal of the American Chemical Society · 2019Article
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Macrocycles are appealing drug candidates due to their high affinity, specificity, and favorable pharmacological properties. In this study, we explored the effects of chemical modifications to a natural product macrocycle upon its activity, 3D geometry, and conformational entropy. We chose thiocillin as a model system, a thiopeptide in the ribosomally encoded family of natural products that exhibits potent antimicrobial effects against Gram-positive bacteria. Since thiocillin is derived from a genetically encoded peptide scaffold, site-directed mutagenesis allows for rapid generation of analogues. To understand thiocillin's structure-activity relationship, we generated a site-saturation mutagenesis library covering each position along thiocillin's macrocyclic ring. We report the identification of eight unique compounds more potent than wild-type thiocillin, the best having an 8-fold improvement in potency. Computational modeling of thiocillin's macrocyclic structure revealed a striking requirement for a low-entropy macrocycle for activity. The populated ensembles of the active mutants showed a rigid structure with few adoptable conformations while inactive mutants showed a more flexible macrocycle which is unfavorable for binding. This finding highlights the importance of macrocyclization in combination with rigidifying post-translational modifications to achieve high-potency binding.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.