‘Mechanistic insights into 5-lipoxygenase inhibition by active principles derived from essential oils of Curcuma species: Molecular docking, ADMET analysis and molecular dynamic simulation study

by Ayushman Gadnayak, Budheswar Dehury, Ananya Nayak, Sudipta Jena, Ambika Sahoo, Pratap Chandra Panda, Asit Ray, Sanghamitra Nayak

Inflammation is caused by a cascade of events, one of which is the metabolism of arachidonic acid, that begins with oxidation by the enzyme 5-lipoxygenase. 5-Lipoxygenase (5-LOX) plays an important role in the inflammation process by synthesizing leukotrienes and several lipid mediators and has emerged as a possible therapeutic target for treatment of inflammatory diseases such as asthma and rheumatoid arthritis. Most of the existing 5-LOX inhibitors are synthetic and exhibit adverse side effects. In view of this, there is need to search for an alternate source of 5-LOX inhibitor with minimal side effects. The essential oil of several species of Curcuma has received considerable attention in recent times in traditional system of medicine especially for treating various inflammatory disorders. Therefore, the present study was carried out to screen the most potential 5-LOX inhibitors from essential oil components of Curcuma species and elucidate their mechanisms of action through computational biology approaches. Twenty-three phytoconstituents derived from the essential oil of Curcuma species were docked and their predictive binding energies were calculated to select the best possible ligand for 5-LOX. The top 8 ranked compounds from docking was tested for drug-likeness properties, bioactivity score, and toxicity analysis. The phytoconstituents such as α-turmerone, β-turmerone, α-terpineol and dihydrocarveolshowed the best binding affinity with 5-LOX and displayed favorable physicochemical properties. Molecular dynamics simulation in POPC lipid bilayers was carried out to understand the intrinsic dynamics and flexibility of the 5-LOX (apo) and 5-LOX-complex (α-terpineol, α-turmerone, β-turmerone and dihydrocarveol) systems. The molecular dynamic results showed that these 4 phytoconstituents interacted stably with the 5-LOX active site residues and the important bonds that were observed in the initial ligand docked compounds did not alter during the course of simulation. In general, our integrative computational approach demonstrated that the natural compounds like α-turmerone, β-turmerone, α-terpineol, and dihydrocarveol could be considered for designing specific anti-inflammatory drugs using structure-based drug design.