Phytosterols demonstrate selective inhibition of COX-2: In-vivo and in-silico studies of Nicotiana tabacum

The inhibition of cyclooxygenase-1 (COX-1) enzyme by Nonsteroidal anti-inflammatory drugs (NSAIDs) exposes the gastrointestinal mucosa to peptic injuries. Selective inhibition of COX-2 generates surpassing anti-inflammatory drug candidates with reduced side effects over current NSAIDs. Phytosterols consumption is reported to decrease the risk of cardiovascular problems. Reports on the selective inhibition of COX-2 by phytosterols are scarce. The present study assesses the anti-inflammatory potentials of phytosterols from Nicotiana tabacum (of the family Solanaceae) through selective inhibition of COX-1 and/or COX-2. Virtual High Throughput Screening (vHTS) and Molecular Docking of phytochemicals from Nicotiana tabacum against the catalytic pockets of COX-1 and COX-2 were used to identify the lead bioactive(s) components of the plant. The hit phytosterols were isolated, histopathological examination of the stomach, in-vivo COX-1/COX-2 mRNAs expression patterns in the liver through reverse transcription-polymerase chain reactions, and enzymes activities of Nicotiana tabacum phytosterol isolates (NTPI) in HCl/ethanol-induced inflammation in Wistar rats were all investigated. Formation of hydrogen bonds favour selective inhibition of COX-2 while hydrophobic interactions favour selective inhibition of COX-1. NTPI demonstrates inhibition of COX-2 by down-regulate the expression of COX-2 mRNA and were ineffective against the expression COX-1 mRNA. NTPI demonstrates hepatoprotective abilities by improving the antioxidant defense system of the liver. Histopathological analyses show NTPI at 50 mg/kg bodyweight regenerates the parietal cells and maintain the gastrointestinal architecture. Drug likeness prediction and ADME toxicity screening show that phytosterols possess good oral bioavailability with no side effects. Phytosterols are selective inhibitors of COX-2, they are hepatoprotective, regenerate parietal cells, and non-toxic.

Keywords: Anti-inflammation; Cyclooxygenase -1 (COX-1) and cyclooxygenase -2 (COX-2); Molecular Docking; Phytosterols; Virtual High Throughput Screening (vHTS).