Short Lecture "Computational investigation of 15-lipoxgenase-1 activation mechanism by different natural products"

15-Lipoxygenase-1 (15LOX1) plays a key role in the formation of specialised pro-resolving mediators (SPMs). It has been shown that 3-O-acetyl-11-keto-β-boswellic acid (AKBA) can stimulate SPM formation via direct binding to an allosteric binding site on 15LOX1.1 This binding site is also suspected of accommodating other natural products that are known for their modulatory effects on leukotriene formation. In this study a series of 33 well-known anti-inflammatory natural products (among them hyperforin, resveratrol, rosmarinic acid and cannabidiol) were investigated for their activating effects on 15LOX1. Biovia’s Discovery Studio (vs 2020) was used to conduct a CHARMm molecular dynamics simulation of a human 15LOX1 homology model (AlphaFold Data Copyright (2022) DeepMind Technologies Limited) with known active AKBA to optimise the conformation of the allosteric binding pocket. A subsequent docking study in GOLD (vs 2020 3.0) was carried out to rationalise the SAR of the novel 15LOX1 activators. One of the most promising candidates was cannabidiol (see [Fig. 1]), displaying robust activation of 15LOX-1 in macrophages. The docking study revealed a consistent binding mode for the most active members of the series, placing them in a cavity close to Arg98 on the membrane binding domain and Arg134 on the catalytic domain. Binding patterns of docking poses within this cavity allowed for discrimination between active and inactive molecules and could be used for activity prediction and lead optimisation in the future within this novel approach for inflammation resolution phytotherapy.

Fig. 1 Predicted binding mode of Cannabidiol in 15-LOX1.

 

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Publication History

Article published online:
16 November 2023