Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.
Computational modeling-based discovery of novel classes of anti-inflammatory drugs that target lanthionine synthetase C-like protein 2.
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DOI：
10.1371/journal.pone.0034643
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Bassaganya-Riera J
中科院分区：
文献类型：
--
作者：
Lu P;Hontecillas R;Horne WT;Carbo A;Viladomiu M;Pedragosa M;Bevan DR;Lewis SN;Bassaganya-Riera J
羊毛硫氨酸合成酶组分C样蛋白2（LANCL 2）是真核生物羊毛硫氨酸合成酶组分C样蛋白家族的成员，参与信号转导和胰岛素增敏。最近，LANCL 2是脱落酸（阿坝）的结合和信号传导的靶标，脱落酸是具有抗糖尿病和抗炎作用的植物激素。本研究的目的是确定LANCL 2作为开发针对炎症性疾病的新药和营养品的潜在治疗靶点的作用。以前，我们进行同源建模，以构建一个三维结构的LANCL 2使用的晶体结构的羊毛硫氨酸合成酶组分C样蛋白1（LANCL 1）作为模板。使用该模型，使用来自NCI（国家癌症研究所）Diversity Set II、ChemBridge、ZINC天然产物和FDA批准的药物数据库的化合物进行基于结构的虚拟筛选。几个潜在的配体进行了鉴定，使用分子对接。为了验证NCI Diversity Set II中排名最高的化合物（NSC 61610）的抗炎功效，使用葡聚糖硫酸钠（DSS）诱导的结肠炎小鼠模型进行了一系列体外和临床前功效研究。我们的研究结果表明，先导化合物NSC 61610在体外以LANCL 2和腺苷酸环化酶/cAMP依赖性方式激活过氧化物酶体增殖物激活受体γ，并通过下调结肠炎性基因表达和促进调节性T细胞应答来改善实验性结肠炎。LANCL 2是炎症性疾病的一个新的治疗靶点。高通量、基于结构的虚拟筛选是一种有效的基于计算的药物设计方法，用于发现基于LANCL 2的抗炎候选药物。
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. 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. 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.
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