Abstract

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.