Human 15‐lipoxygenase‐1 (15‐LOX‐1) is a key enzyme that possesses an important role in (neuro)inflammatory diseases. The pocket of the enzyme plays the role of a chiral catalyst, and therefore chirality could be an important component for the design of effective enzyme inhibitors. To advance our knowledge on this concept, we developed a library of the identified chiral 15‐LOX‐1 inhibitors and applied cheminformatic tools. Our analysis highlighted specific structural elements, which we integrated them in small molecules, and employed them as “smart” tools to effectively navigate the chemical space of previously unexplored regions. To this purpose, we utilized the marine derived natural product phosphoeleganin (PE) among with a small library of synthetic fragment derivatives, including a certain degree of stereochemical diversity. Enzyme inhibition/kinetic and molecular modelling studies has been performed in order to characterize structurally novel PE‐based inhibitors, which proved to present a different type of inhibition with low micromolar potency, according to their structural features. We demonstrate that different warheads work as anchor, and either guide specific stereochemistry, or causing a time‐depended inhibition. Finally, we prove that the positioning of the chiral substituents or/and the favorable stereochemistry can be crucial, as it can lead from active to completely inactive compounds.

中文翻译：

---

通过海洋天然产物研究人类 15-脂氧合酶-1 的催化位点


人类 15-脂氧合酶-1 (15-LOX-1) 是一种关键酶，在（神经）炎症性疾病中发挥重要作用。酶的口袋起着手性催化剂的作用，因此手性可能是设计有效酶抑制剂的重要组成部分。为了增进我们对这一概念的了解，我们开发了一个已鉴定的手性 15-LOX-1 抑制剂的库和应用的化学信息学工具。我们的分析强调了特定的结构元素，我们将它们整合到小分子中，并将它们用作“智能”工具，以有效地导航先前未探索区域的化学空间。为此，我们利用了海洋衍生的天然产物磷酸雅丽素 (PE) 以及一个小型合成片段衍生物库，其中包括一定程度的立体化学多样性。为了表征结构新颖的基于 PE 的抑制剂，已经进行了酶抑制/动力学和分子模型研究，根据其结构特征，这些抑制剂被证明具有低微摩尔效力的不同类型的抑制作用。我们证明了不同的弹头充当锚，或者引导特定的立体化学，或者引起时间依赖性抑制。最后，我们证明手性取代基的定位或/和有利的立体化学可能是至关重要的，因为它可以导致从活性化合物到完全无活性的化合物。