Graduate Program in Pharmaceutical Sciences, Health Sciences Center - CCS, Federal University of Espirito Santo - UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES, Brazil.
Department of Pharmaceutical Sciences, Federal University of Espirito Santo-UFES, Marechal Campos Av., 1468, Vitoria 29043-900, ES, Brazil.
Curr Top Med Chem. 2019;19(30):2795-2804. doi: 10.2174/1568026619666191112105650.
Helicobacter pylori is a gram-negative bacterium related to chronic gastritis, peptic ulcer and gastric carcinoma. During its infection process, promotes excessive inflammatory response, increasing the release of reactive species and inducing the production of pro-inflammatory mediators. Inducible Nitric Oxide Synthase (iNOS) plays a crucial role in the gastric carcinogenesis process and a key mediator of inflammation and host defense systems, which is expressed in macrophages induced by inflammatory stimuli. In chronic diseases such as Helicobacter pylori infections, the overproduction of NO due to the prolonged induction of iNOS is of major concern.
In this sense, the search for potential iNOS inhibitors is a valuable strategy in the overall process of Helicobacter pylori pathogeny.
In silico techniques were applied in the search of interesting compounds against Inducible Nitric Oxide Synthase enzyme in a chemical space of natural products and derivatives from the Analyticon Discovery databases.
The five compounds with the best iNOS inhibition profile were selected for activity and toxicity predictions. Compound 9 (CAS 88198-99-6) displayed significant potential for iNOS inhibition, forming hydrogen bonds with residues from the active site and an ionic interaction with heme. This compound also displayed good bioavailability and absence of toxicity/or from its probable metabolites.
The top-ranked compounds from the virtual screening workflow show promising results regarding the iNOS inhibition profile. The results evidenced the importance of the ionic bonding during docking selection, playing a crucial role in binding and positioning during ligand-target selection for iNOS.
幽门螺杆菌是一种与慢性胃炎、消化性溃疡和胃癌相关的革兰氏阴性细菌。在其感染过程中，促进过度的炎症反应，增加活性物质的释放，并诱导促炎介质的产生。诱导型一氧化氮合酶（iNOS）在胃癌发生过程中起着至关重要的作用，是炎症和宿主防御系统的关键介质，它在炎症刺激诱导的巨噬细胞中表达。在幽门螺杆菌感染等慢性疾病中，由于 iNOS 的长期诱导，NO 的过度产生是一个主要关注点。
从这个意义上说，寻找潜在的 iNOS 抑制剂是幽门螺杆菌病原体发病机制的整体过程中的一个有价值的策略。
在天然产物和 Analyticon Discovery 数据库的衍生物的化学空间中，应用计算机技术搜索针对诱导型一氧化氮合酶酶的有潜力的化合物。
选择了五个具有最佳 iNOS 抑制谱的化合物进行活性和毒性预测。化合物 9（CAS 88198-99-6）显示出对 iNOS 抑制的显著潜力，与活性部位的残基形成氢键，并与血红素发生离子相互作用。该化合物还具有良好的生物利用度和缺乏毒性/从其可能的代谢物。
虚拟筛选工作流程中排名靠前的化合物在 iNOS 抑制谱方面显示出有希望的结果。结果表明，在对接选择过程中离子键的重要性，在配体-靶标选择过程中对 iNOS 的结合和定位起着关键作用。
