Structure-based design of multi-target drugs using the example of dual inhibitors of LTA4 hydrolase and soluble epoxide hydrolase

炎症是一种多途径控制的病理生理状态。炎症过程的中心调节者之一是花生四烯酸级联反应，它控制炎症的开始和主动消退。与选择性化合物相比，花生四烯酸级联反应中涉及的双靶点或多靶点的酶抑制剂具有几个优点，包括比几种药物的组合具有更好的疗效和更简单的药代动力学和药效学特性。不幸的是，合理设计多元药理化合物是一项相当艰巨的任务，而且还没有得到很好的确立。在最初的三年里，我们制定了一种确定合理多靶点药物发现起点的策略，发现了5-脂氧合酶和可溶性环氧化物水解酶的新型抑制剂。基于这些结果，本项目的目标是合理优化多靶标，将其应用于可溶性环氧化物水解酶和白三烯A4水解酶双重抑制剂的设计。我们认为，双重抑制这两种酶将导致慢性炎症条件下积累的抗炎脂质介质的解决。

Inflammation is a pathophysiological state controlled by multiple pathways. One of the central regulators of inflammatory processes is the arachidonic acid cascade, which controls the onset and the active resolution of inflammation. Dual or multi-target inhibitors of enzymes involved in the arachidonic acid cascade have several advantages compared with selective compounds, including improved efficacy and more simple pharmacokinetic and pharmacodynamic properties than a combination of several drugs. Unfortunately, the rational design of polypharmacological compounds is a rather hard task and not well established. In the first three years we developed a strategy for the identification of starting points for rational multi-target drug discovery discovering novel inhibitors of 5-lipoxygenase and soluble epoxide hydrolase. Based on these results, the aim of the proposed project is the rational optimization of multi-target leads, which will be applied to the design of dual inhibitors of soluble epoxide hydrolase and leukotriene A4 hydrolase. We assume that dual inhibition of both enzymes will lead to resolution of chronic inflammatory conditions by accumulation of anti-inflammatory lipid mediators.