Dual synergistic inhibition of COX and LOX by potential chemicals from Indian daily spices investigated through detailed computational studies

Abstract

Cyclooxygenase (COX) and Lipoxygenase (LOX) are essential enzymes for arachidonic acid (AA) to eicosanoids conversion. These AA-derived eicosanoids are essential for initiating immunological responses, causing inflammation, and resolving inflammation. Dual COX/5-LOX inhibitors are believed to be promising novel anti-inflammatory agents. They inhibit the synthesis of prostaglandins (PGs) and leukotrienes (LTs), but have no effect on lipoxin formation. This mechanism of combined inhibition circumvents certain limitations for selective COX-2 inhibitors and spares the gastrointestinal mucosa. Natural products, i.e. spice chemicals and herbs, offer an excellent opportunity for drug discovery. They have proven anti-inflammatory properties. However, the potential of a molecule to be a lead/ drug candidate can be much more enhanced if it has the property of inhibition in a dual mechanism. Synergistic activity is always a better option than the molecule's normal biological activity. Herein, we have explored the dual COX/5-LOX inhibition property of the three major potent phytoconsituents (curcumin, capsaicin, and gingerol) from Indian spices using in silico tools and biophysical techniques in a quest to identify their probable inhibitory role as anti-inflammatory agents. Results revealed the dual COX/5-LOX inhibitory potential of curcumin. Gingerol and capsaicin also revealed favorable results as dual COX/5-LOX inhibitors. Our results are substantiated by target similarity studies, molecular docking, molecular dynamics, energy calculations, DFT, and QSAR studies. In experimental inhibitory (in vitro) studies, curcumin exhibited the best dual inhibitory activities against COX-1/2 and 5-LOX enzymes. Capsaicin and gingerol also showed inhibitory potential against both COX and LOX enzymes. In view of the anti-inflammatory potential these spice chemicals, this research could pave the way for more scientific exploration in this area for drug discovery.

Synthesis of novel carbazole hydrazine-carbothioamide scaffold as potent antioxidant, anticancer and antimicrobial agents

“…These computational techniques, such as molecular docking and drug-likeness analysis, enable researchers to simulate and analyze molecular interactions between potential drug candidates and their biological targets [ 65 ]. By harnessing the power of computational algorithms and predictive models, scientists can expedite the identification of promising drug candidates, optimize their chemical structures for enhanced efficacy and safety, and prioritize compounds for further experimental validation [ 66 ]. Additionally, in silico studies provide valuable insights into the physicochemical properties, pharmacokinetics, and potential biological activities of drug candidates, thereby aiding in the rational design and optimization of novel therapeutics.…”

In vitro Genotoxicity and In silico Docking Analyses of the Essential Oils of Thuja orientalis

“…The molecule was obtained from the RSCB databank in pdb format [72] . The preparation of the dodecamer involved the removal of water molecules, the addition of polar hydrogens, [73] and the application of Kollman Charges. Auto Dock Tools 1.5.6 were used for the preparation [56] …”

Critical review on anti‐inflammation effects of saponins and their molecular mechanisms

“…The inhibition of COX and LOX enzymes plays a crucial role in the modulation of inflammation, as these enzymes are key players in the synthesis of inflammatory mediators. Prostaglandins and leukotrienes, produced by COX and LOX, respectively, contribute to the initiation and propagation of inflammatory responses in the body (Rudrapal et al, 2023). The dual inhibition of COX and LOX is particularly noteworthy, as it addresses multiple pathways in the inflammatory cascade.…”