Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2

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dc.contributor.authorLu, Pinyien
dc.contributor.authorHontecillas, Raquelen
dc.contributor.authorHorne, William T.en
dc.contributor.authorCarbo, Adriaen
dc.contributor.authorViladomiu, Monicaen
dc.contributor.authorPedragosa, Mireiaen
dc.contributor.authorBevan, David R.en
dc.contributor.authorLewis, Stephanie N.en
dc.contributor.authorBassaganya-Riera, Josepen
dc.date.accessioned2016-12-23T14:38:02Zen
dc.date.available2016-12-23T14:38:02Zen
dc.date.issued2012-04-11en
dc.description.abstractBackground: Lanthionine synthetase component C-like protein 2 (LANCL2) is a member of the eukaryotic lanthionine synthetase component C-Like protein family involved in signal transduction and insulin sensitization. Recently, LANCL2 is a target for the binding and signaling of abscisic acid (ABA), a plant hormone with anti-diabetic and anti-inflammatory effects. Methodology/Principal Findings: The goal of this study was to determine the role of LANCL2 as a potential therapeutic target for developing novel drugs and nutraceuticals against inflammatory diseases. Previously, we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of lanthionine synthetase component C-like protein 1 (LANCL1) as a template. Using this model, structure-based virtual screening was performed using compounds from NCI (National Cancer Institute) Diversity Set II, ChemBridge, ZINC natural products, and FDA-approved drugs databases. Several potential ligands were identified using molecular docking. In order to validate the anti-inflammatory efficacy of the top ranked compound (NSC61610) in the NCI Diversity Set II, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate (DSS)-induced colitis. Our findings showed that the lead compound, NSC61610, activated peroxisome proliferator-activated receptor gamma in a LANCL2- and adenylate cyclase/cAMP dependent manner in vitro and ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. Conclusions/Significance: LANCL2 is a novel therapeutic target for inflammatory diseases. High-throughput, structure-based virtual screening is an effective computational-based drug design method for discovering anti-inflammatory LANCL2-based drug candidates.en
dc.description.sponsorshipSupported by award number 5R01AT004308 of the National Center for Complementary and Alternative Medicine at the National Institutes of Health awarded to J.B.-R. and NIAID Contract No. HHSN272201000056C to JBR and funds from the Nutritional Immunology and Molecular Medicine Laboratory. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.description.versionPublished versionen
dc.format.extent? - ? (13) page(s)en
dc.identifier.citationLu P, Hontecillas R, Horne WT, Carbo A, Viladomiu M, et al. (2012) Computational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2. PLoS ONE 7(4): e34643.en
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0034643en
dc.identifier.issn1932-6203en
dc.identifier.issue4en
dc.identifier.urihttp://hdl.handle.net/10919/73809en
dc.identifier.volume7en
dc.languageEnglishen
dc.publisherPLOSen
dc.relation.urihttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000305336600044&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=930d57c9ac61a043676db62af60056c1en
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectinflammatory-bowel-diseaseen
dc.subjecttissue-specific expressionen
dc.subjectregulatory t-cellsen
dc.subjectabscisic-aciden
dc.subjectcellular-sensitivityen
dc.subjectcoupled receptoren
dc.subjecthomology modelsen
dc.subjecthuman lancl2en
dc.subjectppar-gammaen
dc.subjectdockingen
dc.titleComputational Modeling-Based Discovery of Novel Classes of Anti-Inflammatory Drugs That Target Lanthionine Synthetase C-Like Protein 2en
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciencesen
pubs.organisational-group/Virginia Tech/Agriculture & Life Sciences/Biochemistryen
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pubs.organisational-group/Virginia Tech/Faculty of Health Sciencesen
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pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Instituteen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Institute/Researchersen
pubs.organisational-group/Virginia Tech/University Research Institutes/Biocomplexity Institute/SelectedFaculty1en

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