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dc.contributor.authorKonstantinidou, Markella
dc.contributor.authorMagari, Francesca
dc.contributor.authorSutanto, Fandi
dc.contributor.authorHaupenthal, Jörg
dc.contributor.authorJumde, Varsha R
dc.contributor.authorÜnver, M Yagiz
dc.contributor.authorHeine, Andreas
dc.contributor.authorCamacho, Carlos Jamie
dc.contributor.authorHirsch, Anna K H
dc.contributor.authorKlebe, Gerhard
dc.contributor.authorDömling, Alexander
dc.date.accessioned2020-05-28T10:01:40Z
dc.date.available2020-05-28T10:01:40Z
dc.date.issued2020-03-18
dc.identifier.citationChemMedChem. 2020;15(8):680‐684. doi:10.1002/cmdc.202000024.en_US
dc.identifier.pmid32187447
dc.identifier.doi10.1002/cmdc.202000024
dc.identifier.urihttp://hdl.handle.net/10033/622277
dc.description.abstractPharmacophore 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.en_US
dc.language.isoenen_US
dc.publisherWiley-VCHen_US
dc.relation: info:eu-repo/grantAgreement/EC/H2020/757913en_US
dc.rightsopenAccessen_US
dc.rightsAttribution-NonCommercial-ShareAlike 4.0 International*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subjectMCR chemistryen_US
dc.subjectaspartic proteaseen_US
dc.subjectcrystal structuresen_US
dc.subjectdocking protocolen_US
dc.subjecthydrazine-tetrazolesen_US
dc.titleRapid Discovery of Aspartyl Protease Inhibitors Using an Anchoring Approach.en_US
dc.typeArticleen_US
dc.identifier.eissn1860-7187
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalChemMedChemen_US
dc.source.volume15
dc.source.issue8
dc.source.beginpage680
dc.source.endpage684
refterms.dateFOA2020-05-28T10:01:41Z
dc.source.journaltitleChemMedChem
dc.source.countryInternational
dc.source.countryGermany


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