ArticleAngewandte Chemie (International ed. in English)2016
Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry.
Article in Angewandte Chemie (International ed. in English), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 67 citations in OpenAlex.
- Exploration of novel β-lactamase inhibitors against Klebsiella pneumoniae using fragment-based drug discovery approach.Molecular diversity · 2026Article
- Optimization of galectin-3 binding agents by in situ multiple compound synthesis and native mass spectrometry.Scientific reports · 2026Article
- Reflectometric-based sensor arrays for the screening of kinase-inhibitor interactions and kinetic determination.Analytical and bioanalytical chemistry · 2025Article
- Designing of fragment based inhibitors with improved activity againstSaudi journal of biological sciences · 2024Article
- Applications of Solution NMR in Drug Discovery.Molecules (Basel, Switzerland) · 2021Review
- Identification of β-strand mediated protein-protein interaction inhibitors using ligand-directed fragment ligation.Chemical science · 2021Article
- Schistosomiasis Drug Discovery in the Era of Automation and Artificial Intelligence.Frontiers in immunology · 2021Review
- Protein-Templated Hit Identification through an Ugi Four-Component Reaction*.Chemistry (Weinheim an der Bergstrasse, Germany) · 2020Article
- Protein-Directed Dynamic Combinatorial Chemistry: An Efficient Strategy in Drug Design.ACS omega · 2020Review
- SyntaLinker: automatic fragment linking with deep conditional transformer neural networks.Chemical science · 2020Article
- Application of Fragment-Based Drug Discovery to Versatile Targets.Frontiers in molecular biosciences · 2020Review
- Concepts and Core Principles of Fragment-Based Drug Design.Molecules (Basel, Switzerland) · 2019Review
- Protein-Templated Dynamic Combinatorial Chemistry: Brief Overview and Experimental Protocol.European journal of organic chemistry · 2019Review
- A Candidate for Multitopic Probes for Ligand Discovery in Dynamic Combinatorial Chemistry.Molecules (Basel, Switzerland) · 2019Article
- Discovery of a Biologically Active Bromodomain Inhibitor by Target-Directed Dynamic Combinatorial Chemistry.ACS medicinal chemistry letters · 2018Article
- Insights into the Impact of Linker Flexibility and Fragment Ionization on the Design of CK2 Allosteric Inhibitors: Comparative Molecular Dynamics Simulation Studies.International journal of molecular sciences · 2018Article
- Redox Control over Acyl Hydrazone Photoswitches.Journal of the American Chemical Society · 2017Article
- Proteintemplat-gesteuerte Fragmentligationen - von der molekularen Erkennung zur Wirkstofffindung.Angewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2017Article
- Protein-Templated Fragment Ligations-From Molecular Recognition to Drug Discovery.Angewandte Chemie (International ed. in English) · 2017Review
- Fragment-Based Drug Design Facilitated by Protein-Templated Click Chemistry: Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.Chemistry (Weinheim an der Bergstrasse, Germany) · 2016Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Fragment-based drug design (FBDD) affords active compounds for biological targets. While there are numerous reports on FBDD by fragment growing/optimization, fragment linking has rarely been reported. Dynamic combinatorial chemistry (DCC) has become a powerful hit-identification strategy for biological targets. We report the synergistic combination of fragment linking and DCC to identify inhibitors of the aspartic protease endothiapepsin. Based on X-ray crystal structures of endothiapepsin in complex with fragments, we designed a library of bis-acylhydrazones and used DCC to identify potent inhibitors. The most potent inhibitor exhibits an IC50 value of 54 nm, which represents a 240-fold improvement in potency compared to the parent hits. Subsequent X-ray crystallography validated the predicted binding mode, thus demonstrating the efficiency of the combination of fragment linking and DCC as a hit-identification strategy. This approach could be applied to a range of biological targets, and holds the potential to facilitate hit-to-lead optimization.
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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.