Pilger, Jens

[["dc.bibliographiccitation.firstpage","6511"],["dc.bibliographiccitation.issue","22"],["dc.bibliographiccitation.journal","Angewandte Chemie International Edition"],["dc.bibliographiccitation.lastpage","6515"],["dc.bibliographiccitation.volume","54"],["dc.contributor.author","Pilger, Jens"],["dc.contributor.author","Mazur, Adam"],["dc.contributor.author","Monecke, Peter"],["dc.contributor.author","Schreuder, Herman"],["dc.contributor.author","Elshorst, Bettina"],["dc.contributor.author","Bartoschek, Stefan"],["dc.contributor.author","Langer, Thomas"],["dc.contributor.author","Schiffer, Alexander"],["dc.contributor.author","Krimm, Isabelle"],["dc.contributor.author","Wegstroth, Melanie"],["dc.contributor.author","Lee, Donghan"],["dc.contributor.author","Hessler, Gerhard"],["dc.contributor.author","Wendt, K. Ulrich"],["dc.contributor.author","Becker, Stefan"],["dc.contributor.author","Griesinger, Christian"],["dc.date.accessioned","2017-09-07T11:44:23Z"],["dc.date.available","2017-09-07T11:44:23Z"],["dc.date.issued","2015"],["dc.description.abstract","Structure-based drug design (SBDD) is a powerful and widely used approach to optimize affinity of drug candidates. With the recently introduced INPHARMA method, the binding mode of small molecules to their protein target can be characterized even if no spectroscopic information about the protein is known. Here, we show that the combination of the spin-diffusion-based NMR methods INPHARMA, trNOE, and STD results in an accurate scoring function for docking modes and therefore determination of protein-ligand complex structures. Applications are shown on the model system protein kinaseA and the drug targets glycogen phosphorylase and soluble epoxide hydrolase (sEH). Multiplexing of several ligands improves the reliability of the scoring function further. The new score allows in the case of sEH detecting two binding modes of the ligand in its binding site, which was corroborated by X-ray analysis."],["dc.identifier.doi","10.1002/anie.201500671"],["dc.identifier.gro","3141898"],["dc.identifier.isi","000355229800018"],["dc.identifier.pmid","25877959"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/2300"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10 / Funder: BMBF [1615870A]"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.eissn","1521-3773"],["dc.relation.issn","1433-7851"],["dc.title","A Combination of Spin Diffusion Methods for the Determination of Protein-Ligand Complex Structural Ensembles"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","3543"],["dc.bibliographiccitation.issue","9"],["dc.bibliographiccitation.journal","Chemical Science"],["dc.bibliographiccitation.lastpage","3551"],["dc.bibliographiccitation.volume","5"],["dc.contributor.author","Masini, T."],["dc.contributor.author","Pilger, Jens"],["dc.contributor.author","Kroezen, B. S."],["dc.contributor.author","Illarionov, B."],["dc.contributor.author","Lottmann, Philip"],["dc.contributor.author","Fischer, M."],["dc.contributor.author","Griesinger, Christian"],["dc.contributor.author","Hirsch, A. K. H."],["dc.date.accessioned","2017-09-07T11:45:35Z"],["dc.date.available","2017-09-07T11:45:35Z"],["dc.date.issued","2014"],["dc.description.abstract","We applied for the first time an innovative ligand-based NMR methodology (STI) to a medicinal-chemistry project aimed at the development of inhibitors for the enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXS). DXS is the first enzyme of the 2C-methyl-D-erythritol-4-phosphate (MEP) pathway, present in most bacteria (and not in humans) and responsible for the synthesis of the essential isoprenoid precursors. We designed de novo a first generation of fragments, using Deinococcus radiodurans DXS as a model enzyme, targeting the thiamine diphosphate (TDP) pocket of DXS whilst also exploring the putative substrate-binding pocket, where selectivity over other human TDP-dependent enzymes could be gained. The STI methodology - suitable for weak binders - was essential to determine the binding mode in solution of one of the fragments, circumventing the requirement for an X-ray co-crystal structure, which is known to be particularly challenging for this specific enzyme and in general for weak binders. Based on this finding, we carried out fragment growing and optimisation, which led to a threefold more potent fragment, about as potent as the well-established thiamine analogue deazathiamine. The STI methodology proved therefore its strong potential as a tool to support medicinal-chemistry projects in their early stages, especially when dealing with weak binders."],["dc.identifier.doi","10.1039/c4sc00588k"],["dc.identifier.gro","3142064"],["dc.identifier.isi","000340695800026"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/4145"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.status","final"],["dc.notes.submitter","PUB_WoS_Import"],["dc.publisher","Royal Soc Chemistry"],["dc.relation.eissn","2041-6539"],["dc.relation.issn","2041-6520"],["dc.title","De novo fragment-based design of inhibitors of DXS guided by spin-diffusion-based NMR spectroscopy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","795"],["dc.bibliographiccitation.issue","6"],["dc.bibliographiccitation.journal","Acta Neuropathologica"],["dc.bibliographiccitation.lastpage","813"],["dc.bibliographiccitation.volume","125"],["dc.contributor.author","Wagner, J."],["dc.contributor.author","Ryazanov, S."],["dc.contributor.author","Leonov, A."],["dc.contributor.author","Levin, J."],["dc.contributor.author","Shi, S."],["dc.contributor.author","Schmidt, F."],["dc.contributor.author","Prix, C."],["dc.contributor.author","Pan-Montojo, F."],["dc.contributor.author","Bertsch, U."],["dc.contributor.author","Mitteregger-Kretzschmar, G."],["dc.contributor.author","Geissen, M."],["dc.contributor.author","Eiden, M."],["dc.contributor.author","Leidel, F."],["dc.contributor.author","Hirschberger, T."],["dc.contributor.author","Deeg, A. A."],["dc.contributor.author","Krauth, J. J."],["dc.contributor.author","Zinth, W."],["dc.contributor.author","Tavan, P."],["dc.contributor.author","Pilger, J."],["dc.contributor.author","Zweckstetter, M."],["dc.contributor.author","Frank, T."],["dc.contributor.author","Bähr, M."],["dc.contributor.author","Weishaupt, J. H."],["dc.contributor.author","Uhr, M."],["dc.contributor.author","Urlaub, H."],["dc.contributor.author","Teichmann, U."],["dc.contributor.author","Samwer, M."],["dc.contributor.author","Bötzel, K."],["dc.contributor.author","Groschup, M."],["dc.contributor.author","Kretzschmar, Hans"],["dc.contributor.author","Griesinger, C."],["dc.contributor.author","Giese, A."],["dc.date.accessioned","2017-09-07T11:47:41Z"],["dc.date.available","2017-09-07T11:47:41Z"],["dc.date.issued","2013"],["dc.description.abstract","In neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of alpha-synuclein (alpha-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and alpha-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood-brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases."],["dc.identifier.doi","10.1007/s00401-013-1114-9"],["dc.identifier.gro","3142347"],["dc.identifier.isi","000319357900002"],["dc.identifier.pmid","23604588"],["dc.identifier.purl","https://resolver.sub.uni-goettingen.de/purl?gs-1/10301"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/7275"],["dc.language.iso","en"],["dc.notes.intern","WoS Import 2017-03-10"],["dc.notes.intern","Merged from goescholar"],["dc.notes.status","zu prüfen"],["dc.notes.submitter","PUB_WoS_Import"],["dc.relation.issn","0001-6322"],["dc.rights","Goescholar"],["dc.rights.uri","https://goescholar.uni-goettingen.de/licenses"],["dc.title","Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dc.type.peerReviewed","yes"],["dc.type.subtype","original"],["dc.type.version","published_version"],["dspace.entity.type","Publication"]]