Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Etiler, 06560 Yenimahalle, Ankara, Turkey.
Laboratory of Molecular Modeling, Evias Pharmaceutical R&D Ltd., Gazi Teknopark G1-101, 06830 Golbasi, Ankara, Turkey.
J Chem Inf Model. 2020 Mar 23;60(3):1737-1748. doi: 10.1021/acs.jcim.9b00941. Epub 2020 Feb 24.
Leukotrienes (LTs) are proinflammatory mediators derived from arachidonic acid (AA), which play significant roles in inflammatory diseases. The 5-lipoxygenase-activating protein (FLAP) is an integral membrane protein, which is essential for the initial step in LT biosynthesis. The aim of this study was to discover novel and chemically diverse FLAP inhibitors for treatment of inflammatory diseases requiring anti-LT therapy. Both ligand- and structure-based approaches were applied to explain the activities of known FLAP inhibitors in relation to their predicted binding modes. We gained valuable insights into the binding modes of the inhibitors by molecular modeling and generated a multistep virtual screening (VS) workflow in which 6.2 million compounds were virtually screened, and the molecular hypotheses were validated by testing VS-hit compounds biologically. The most potent hit compounds showed significant inhibition of FLAP-dependent cellular LT biosynthesis with IC values in the range from 0.13 to 0.87 μM. Collectively, this study provided novel bioactive chemotypes with potential for further development as effective anti-inflammatory drugs.
白三烯（LTs）是源自花生四烯酸（AA）的促炎介质，在炎症性疾病中发挥重要作用。5-脂氧合酶激活蛋白（FLAP）是一种完整的膜蛋白，是 LT 生物合成初始步骤所必需的。本研究旨在发现新型、化学多样性的 FLAP 抑制剂，用于治疗需要抗 LT 治疗的炎症性疾病。本研究同时应用配体和基于结构的方法来解释已知 FLAP 抑制剂的活性与其预测的结合模式之间的关系。通过分子建模，我们深入了解了抑制剂的结合模式，并生成了一个多步骤虚拟筛选（VS）工作流程，其中对 620 万个化合物进行了虚拟筛选，并通过生物测试验证了 VS 命中化合物的分子假说。最有效的命中化合物显示出对 FLAP 依赖性细胞 LT 生物合成的显著抑制作用，IC 值在 0.13 至 0.87 μM 范围内。总的来说，这项研究提供了具有潜在进一步发展为有效抗炎药物的新型生物活性化学型。
