'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

Abstract

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.

Fig 1

Intermolecular contact analysis of the top four-ligands (A: B: C: D:) with 5-LOX protein obtained from docking using Glide displaying various non-bonded contacts. The image was rendered using PyMOL. The hydrogen bonds are shown in dotted lines. The left panel displays the structurally superimposed view of the top ranked 5-LOX-ligand complexes obtained from docking.

Fig 2

The electrostatic surface potential map of the 5-LOX protein (A) and the protein-ligand complexes (B) generated using APBS-plugin in PyMOL. Different colors like blue, red, and white epitomize positively charged, negatively charged, and neutral surface patches respectively of the protein and complexes.

Fig 3. The membrane aligned view of the complete 5-LOX protein and membrane protein (shown in cartoon representation) on the surface of POPC lipid bilayer (waters shown in surface format (white), lipids in sphere format, and lipid head groups in red sphere).

Fig 4. Intrinsic dynamics stability and flexibilities of the 5-LOX complex systems during all-atoms MD simulation of 100 ns.

(A) Backbone RMSD of the five systems (including apo form and holo form of 5-LOX) membrane-water system during 500-ns MD simulations. (B) The Cα-root mean squared fluctuation (RMSF) profile of each amino acid of 5-LOX apo and holo systems during simulation in the lipid bilayer system.

Fig 5

Interaction fraction of amino acids from 5-LOX complex systems involved in ligand recognition during 100 ns MD (A: B: C: D:).

Fig 6. Structural superimposed view of the pre (green) and post-MD (cyan) snapshots displaying the orientation of ligands within the binding pocket of 5-LOX protein.

Fig 7. Interaction of ligands with 5-LOX protein obtained from the MD trajectories upon clustering.

The protein is shown in cartoon format and the ligands are shown in ball-stick format. The interacting amino acids are labelled in black.