Lu, PinyiHontecillas, RaquelHorne, William T.Carbo, AdriaViladomiu, MonicaPedragosa, MireiaBevan, David R.Lewis, Stephanie N.Bassaganya-Riera, Josep2016-12-232016-12-232012-04-11Lu 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): e34643.1932-6203http://hdl.handle.net/10919/73809Background: 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.? - ? (13) page(s)Creative Commons Attribution 4.0 Internationalinflammatory-bowel-diseasetissue-specific expressionregulatory t-cellsabscisic-acidcellular-sensitivitycoupled receptorhomology modelshuman lancl2ppar-gammadockingArticle - Refereedhttps://doi.org/10.1371/journal.pone.003464374