000163399 001__ 163399
000163399 005__ 20240320115517.0
000163399 0247_ $$2doi$$a10.1021/jacs.1c07591
000163399 0247_ $$2pmid$$apmid:35130691
000163399 0247_ $$2pmc$$apmc:PMC8855421
000163399 0247_ $$2ISSN$$a0002-7863
000163399 0247_ $$2ISSN$$a1520-5126
000163399 0247_ $$2ISSN$$a1943-2984
000163399 0247_ $$2altmetric$$aaltmetric:122591676
000163399 037__ $$aDZNE-2022-00161
000163399 041__ $$aEnglish
000163399 082__ $$a540
000163399 1001_ $$aRobustelli, Paul$$b0
000163399 245__ $$aMolecular Basis of Small-Molecule Binding to α-Synuclein.
000163399 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2022
000163399 3367_ $$2DRIVER$$aarticle
000163399 3367_ $$2DataCite$$aOutput Types/Journal article
000163399 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1655210655_923
000163399 3367_ $$2BibTeX$$aARTICLE
000163399 3367_ $$2ORCID$$aJOURNAL_ARTICLE
000163399 3367_ $$00$$2EndNote$$aJournal Article
000163399 500__ $$a(CC BY-NC-ND)
000163399 520__ $$aIntrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-time-scale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson's disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.
000163399 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
000163399 588__ $$aDataset connected to CrossRef, PubMed, , Journals: pub.dzne.de
000163399 650_7 $$2NLM Chemicals$$aIntrinsically Disordered Proteins
000163399 650_7 $$2NLM Chemicals$$aLigands
000163399 650_7 $$2NLM Chemicals$$aSmall Molecule Libraries
000163399 650_7 $$2NLM Chemicals$$aalpha-Synuclein
000163399 650_7 $$084477-87-2$$2NLM Chemicals$$a1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
000163399 650_7 $$0Q0CH43PGXS$$2NLM Chemicals$$afasudil
000163399 650_2 $$2MeSH$$a1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: analogs & derivatives
000163399 650_2 $$2MeSH$$a1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: chemistry
000163399 650_2 $$2MeSH$$a1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: metabolism
000163399 650_2 $$2MeSH$$aAmino Acid Sequence
000163399 650_2 $$2MeSH$$aHydrogen Bonding
000163399 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: chemistry
000163399 650_2 $$2MeSH$$aIntrinsically Disordered Proteins: metabolism
000163399 650_2 $$2MeSH$$aLigands
000163399 650_2 $$2MeSH$$aMolecular Conformation
000163399 650_2 $$2MeSH$$aMolecular Dynamics Simulation
000163399 650_2 $$2MeSH$$aProtein Binding
000163399 650_2 $$2MeSH$$aSmall Molecule Libraries: chemistry
000163399 650_2 $$2MeSH$$aSmall Molecule Libraries: metabolism
000163399 650_2 $$2MeSH$$aalpha-Synuclein: metabolism
000163399 7001_ $$0P:(DE-2719)2812657$$aIbanez de Opakua, Alain$$b1$$udzne
000163399 7001_ $$aCampbell-Bezat, Cecily$$b2
000163399 7001_ $$00000-0001-9876-9552$$aGiordanetto, Fabrizio$$b3
000163399 7001_ $$aBecker, Stefan$$b4
000163399 7001_ $$0P:(DE-2719)2810591$$aZweckstetter, Markus$$b5$$udzne
000163399 7001_ $$aPan, Albert C$$b6
000163399 7001_ $$00000-0001-8265-5761$$aShaw, David E$$b7
000163399 773__ $$0PERI:(DE-600)1472210-0$$a10.1021/jacs.1c07591$$gVol. 144, no. 6, p. 2501 - 2510$$n6$$p2501 - 2510$$tJournal of the American Chemical Society$$v144$$x1520-5126$$y2022
000163399 8564_ $$uhttps://pub.dzne.de/record/163399/files/DZNE-2022-00161.pdf$$yOpenAccess
000163399 8564_ $$uhttps://pub.dzne.de/record/163399/files/DZNE-2022-00161.pdf?subformat=pdfa$$xpdfa$$yOpenAccess
000163399 909CO $$ooai:pub.dzne.de:163399$$pdnbdelivery$$pdriver$$pVDB$$popen_access$$popenaire
000163399 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2812657$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b1$$kDZNE
000163399 9101_ $$0I:(DE-588)1065079516$$6P:(DE-2719)2810591$$aDeutsches Zentrum für Neurodegenerative Erkrankungen$$b5$$kDZNE
000163399 9131_ $$0G:(DE-HGF)POF4-352$$1G:(DE-HGF)POF4-350$$2G:(DE-HGF)POF4-300$$3G:(DE-HGF)POF4$$4G:(DE-HGF)POF$$aDE-HGF$$bGesundheit$$lNeurodegenerative Diseases$$vDisease Mechanisms$$x0
000163399 9141_ $$y2022
000163399 915__ $$0StatID:(DE-HGF)0200$$2StatID$$aDBCoverage$$bSCOPUS$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0300$$2StatID$$aDBCoverage$$bMedline$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)1050$$2StatID$$aDBCoverage$$bBIOSIS Previews$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)1190$$2StatID$$aDBCoverage$$bBiological Abstracts$$d2021-01-30
000163399 915__ $$0StatID:(DE-HGF)0600$$2StatID$$aDBCoverage$$bEbsco Academic Search$$d2022-11-09
000163399 915__ $$0LIC:(DE-HGF)CCBYNCND4$$2HGFVOC$$aCreative Commons Attribution-NonCommercial-NoDerivs CC BY-NC-ND 4.0
000163399 915__ $$0StatID:(DE-HGF)9915$$2StatID$$aIF >= 15$$bJ AM CHEM SOC : 2021$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)1200$$2StatID$$aDBCoverage$$bChemical Reactions$$d2021-01-30
000163399 915__ $$0StatID:(DE-HGF)1150$$2StatID$$aDBCoverage$$bCurrent Contents - Physical, Chemical and Earth Sciences$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0113$$2StatID$$aWoS$$bScience Citation Index Expanded$$d2021-01-30
000163399 915__ $$0StatID:(DE-HGF)1210$$2StatID$$aDBCoverage$$bIndex Chemicus$$d2021-01-30
000163399 915__ $$0StatID:(DE-HGF)1030$$2StatID$$aDBCoverage$$bCurrent Contents - Life Sciences$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0510$$2StatID$$aOpenAccess
000163399 915__ $$0StatID:(DE-HGF)0150$$2StatID$$aDBCoverage$$bWeb of Science Core Collection$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0030$$2StatID$$aPeer Review$$bASC$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0100$$2StatID$$aJCR$$bJ AM CHEM SOC : 2021$$d2022-11-09
000163399 915__ $$0StatID:(DE-HGF)0160$$2StatID$$aDBCoverage$$bEssential Science Indicators$$d2021-01-30
000163399 915__ $$0StatID:(DE-HGF)0420$$2StatID$$aNationallizenz$$d2022-11-09$$wger
000163399 915__ $$0StatID:(DE-HGF)0199$$2StatID$$aDBCoverage$$bClarivate Analytics Master Journal List$$d2022-11-09
000163399 9201_ $$0I:(DE-2719)1410001$$kAG Zweckstetter$$lStructural Biology in Dementia$$x0
000163399 980__ $$ajournal
000163399 980__ $$aVDB
000163399 980__ $$aUNRESTRICTED
000163399 980__ $$aI:(DE-2719)1410001
000163399 9801_ $$aFullTexts