title: Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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
  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.
authors.affiliation: Center for Modeling Immunity to Enteric Pathogens, Virginia Tech, Blacksburg, Virginia, United States of America. lpy0526@vbi.vt.edu
authors.forename: Pinyi
authors.initials: P
authors.lastname: Lu
authors.forename: Raquel
authors.initials: R
authors.lastname: Hontecillas
authors.forename: William T
authors.initials: WT
authors.lastname: Horne
authors.forename: Adria
authors.initials: A
authors.lastname: Carbo
authors.forename: Monica
authors.initials: M
authors.lastname: Viladomiu
authors.forename: Mireia
authors.initials: M
authors.lastname: Pedragosa
authors.forename: David R
authors.initials: DR
authors.lastname: Bevan
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Lewis
authors.forename: Josep
authors.initials: J
authors.lastname: Bassaganya-Riera
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003198:Computer Simulation; D000242:Cyclic AMP / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D028044:Phosphate-Binding Proteins; D011487:Protein Conformation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D014584:User-Computer Interface
chemical_list: D000893:Anti-Inflammatory Agents; C572254:LANCL2 protein, mouse; D008565:Membrane Proteins; D047495:PPAR gamma; D028044:Phosphate-Binding Proteins; D011956:Receptors, Cell Surface; D000242:Cyclic AMP; D000262:Adenylyl Cyclases