Screening of potent inhibitor from Aquilaria malaccensis Lam. against arachidonic inflammatory enzymes: an insight from molecular docking, ADMET, molecular dynamics simulation and MM-PBSA approaches

Abstract

The three primary enzymes COX (cyclooxygenase), LOX (lipoxygenase) and CYT-P450 (cytochrome P450), which are part of the arachidonic inflammatory pathway, play crucial role in the development of asthma, rheumatoid arthritis and cardiovascular diseases. Ethnomedicinally, plant-derived chemicals have a major role in the treatment of fatal illnesses. Aquilaria malaccensis Lam. widely known as agarwood is prized for its fragrance and therapeutic properties. The phytochemicals and extracts of this plant have significant healing properties in the treatment of serious illnesses. In the current work, an in-silico approach including molecular docking, ADMET (absorption, distribution, metabolism, excretion and toxicity), molecular dynamics (MD) simulation and molecular mechanics/Poisson-Boltzmann surface area (MM-PBSA) was performed to screen 33 bioactive compounds from this plant against COX-2 and 5-LOX in order to find the most effective inhibitor. 2-(2-Phenylethyl)chromone was found to inhibit both 5-LOX and COX-2, showing the highest binding affinities (-9.1 kcal/mol and -9.0 kcal/mol, respectively) than standard Ibuprofen and nordihydroguaiaretic acid (NDGA). 2-(2-Phenylethyl)chromone showed the highest drug-likeness score and low risk of toxicity compared to other phytochemicals. MD modeling and MM-PBSA calculations showed that 2-(2-Phenylethyl)chromone had a strong persistent binding interaction with 5-LOX than COX-2, and this interaction is comparable to the bounded standards Ibuprofen and NDGA. From this study, we may infer that the 2-(2-Phenylethyl)chromone can serve as a potent inhibitor and has scope to be employed in the treatment of inflammatory ailments.Communicated by Ramaswamy H. Sarma.

Keywords: 2-(2-Phenylethyl)chromone; 5-LOX; ADMET; Aquilaria malaccensis; COX-2; MM-PBSA; molecular dynamics.