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

BackgroundLanthionine 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 FindingsThe 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/SignificanceLANCL2 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.背景 羊毛硫氨酸合成酶组分C样蛋白2（LANCL2）属于真核生物羊毛硫氨酸合成酶组分C样蛋白家族，参与信号转导与胰岛素增敏过程。近年来研究发现，LANCL2是脱落酸（abscisic acid，ABA）结合与信号转导的靶点，而脱落酸是一种兼具抗糖尿病与抗炎活性的植物激素。 研究方法与主要发现 本研究旨在明确LANCL2作为潜在治疗靶点的作用，以期开发针对炎症性疾病的新型药物与营养保健品。此前，本团队以羊毛硫氨酸合成酶组分C样蛋白1（LANCL1）的晶体结构为模板，通过同源建模法构建了LANCL2的三维结构。基于该模型，本研究针对美国国家癌症研究所（National Cancer Institute，NCI）多样性化合物库II、ChemBridge、ZINC天然产物库以及美国食品药品监督管理局（Food and Drug Administration，FDA）获批药物数据库中的化合物开展了基于结构的虚拟筛选。通过分子对接技术筛选得到多个潜在配体。为验证NCI多样性化合物库II中排名首位的化合物NSC61610的抗炎活性，本研究采用葡聚糖硫酸钠（dextran sodium sulfate，DSS）诱导的结肠炎小鼠模型，开展了一系列体外实验与临床前药效学研究。本研究结果显示，先导化合物NSC61610在体外可通过LANCL2依赖、腺苷酸环化酶/环磷酸腺苷（cAMP）依赖的方式激活过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor gamma，PPARγ），并通过下调结肠炎症相关基因的表达、促进调节性T细胞应答，改善实验性结肠炎。 结论与意义 LANCL2是治疗炎症性疾病的新型治疗靶点。基于结构的高通量虚拟筛选是一种高效的计算机辅助药物设计方法，可用于发掘靶向LANCL2的抗炎候选药物。