In-silico identification of COX-2 inhibitory phytochemicals from traditional medicinal plants: molecular docking, dynamics, and safety predictions.

Inflammation is an essential biological response that facilitates tissue repair and immune defense; however, chronic inflammation is associated with numerous pathological conditions, including cardiovascular diseases, autoimmune disorders, and cancer. Cyclooxygenase-2 (COX-2) is a key enzyme in this process, catalyzing the synthesis of pro-inflammatory prostaglandins, thus representing a critical target for anti-inflammatory therapies. Conventional COX-2 inhibitors, particularly non-steroidal anti-inflammatory drugs (NSAIDs), often have significant side effects, creating an urgent need for safer alternatives. This in-silico study evaluates the binding affinities of bioactive compounds from Gmelina arborea, Coriandrum sativum, Glycyrrhiza glabra, Terminalia chebula, Solanum nigrum, Vernonia cinerea, Portulaca oleracea, Azadirachta indica, and Thespesia populnea to the COX-2 receptor. Molecular docking and dynamics simulations identified solasonine, solamargine, rutin, and glycyrrhizin as having binding affinities ranging from - 9.40 to - 8.50 kcal/mol, exceeding that of the standard NSAID diclofenac (- 5.68 kcal/mol). While these docking results provide valuable insights, further in-vitro validation is necessary. Stability analysis of ligand-receptor complexes showed minimal structural fluctuations. Moreover, cardiotoxicity predictions indicated that solamargine, rutin, and glycyrrhizin present a lower risk compared to diclofenac. ADMET profiling highlighted favorable pharmacokinetic properties for rutin, suggesting its potential as a promising COX-2 inhibitor with a beneficial safety profile. Subsequent MM-GBSA calculations revealed binding free energy values of - 11.316 kcal/mol for rutin and - 35.190 kcal/mol for diclofenac, indicating strong binding interactions. Overall, this study underscores the potential of these natural compounds as safer alternatives in anti-inflammatory therapy, paving the way for future experimental validation and clinical application.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00407-4.