Rapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach.
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Authors
Konstantinidou, MarkellaMagari, Francesca
Sutanto, Fandi
Haupenthal, Jörg
Jumde, Varsha R
Ünver, M Yagiz
Heine, Andreas
Camacho, Carlos Jamie
Hirsch, Anna K H
Klebe, Gerhard
Dömling, Alexander
Issue Date
2020-03-18
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Show full item recordAbstract
Pharmacophore searches that include anchors, fragments contributing above average to receptor binding, combined with one-step syntheses are a powerful approach for the fast discovery of novel bioactive molecules. Here, we are presenting a pipeline for the rapid and efficient discovery of aspartyl protease inhibitors. First, we hypothesized that hydrazine could be a multi-valent warhead to interact with the active site Asp carboxylic acids. We incorporated the hydrazine anchor in a multicomponent reaction and created a large virtual library of hydrazine derivatives synthetically accessible in one-step. Next, we performed anchor-based pharmacophore screening of the libraries and resynthesized top-ranked compounds. The inhibitory potency of the molecules was finally assessed by an enzyme activity assay and the binding mode confirmed by several soaked crystal structures supporting the validity of the hypothesis and approach. The herein reported pipeline of tools will be of general value for the rapid generation of receptor binders beyond Asp proteases.Citation
ChemMedChem. 2020;15(8):680‐684. doi:10.1002/cmdc.202000024.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.Publisher
Wiley-VCHJournal
ChemMedChemPubMed ID
32187447Type
ArticleLanguage
enEISSN
1860-7187ae974a485f413a2113503eed53cd6c53
10.1002/cmdc.202000024
Scopus Count
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