Identification of new potential cyclooxygenase-2 inhibitors via structure-based virtual screening, molecular dynamics and pharmacokinetic modelling

Non-steroidal anti-inflammatory drugs (NSAIDs) are a class of drugs commonly used worldwide for their analgesic and antipyretic effects. However, an overdose of NSAIDs can have negative effects on various systems, including the cardiovascular, gastrointestinal, hepatic, renal and neural systems. The search for new, safer and more effective anti-inflammatory agents has now become a necessity. The aim of the present study is to identify new natural compounds that act against cyclooxygenase-2 (COX-2), one of the main anti-inflammatory targets, by means of computational approaches. For this purpose, molecular docking and MM/GBSA binding free energy calculations were utilized to discover new natural inhibitors for COX-2. In addition, several prediction tools, such as SwissADME server, QikProp and Pro-Tox II were used in this study to elucidate the pharmacokinetic properties, drug-likeness ability, safety and the lethal dose (LD50) of the studied compounds.

The results of molecular docking have indicated that among all phytochemicals under examination, Canniprene, Oroxylin A and Luteolin have shown high docking score and binding affinity toward COX-2 (-10.587, -10.254 and -9.494 Kcal.mol^-1, respectively) when compared with the reference inhibitor. Moreover, the top hits demonstrated stability during molecular dynamics simulation and were found to conform to drug-like rules with good bioavailability. Toxicity parameters of the best hits indicate that these compounds could be safe COX-2 inhibitors, but further in vitro and in vivo studies are needed to confirm these findings.