Discovery of Novel Human COX-2 Inhibitors From the Lotus Natural Products Database: An Integrated in Silico Approach

Cyclooxygenase-2 (COX-2) is a key enzyme involved in the inflammatory pathway and represents an important therapeutic target for the treatment of inflammatory diseases. This study aimed to identify potential natural inhibitors of human COX-2 from the LOTUS natural products database using an in silico drug discovery approach. A library of 276,518 natural compounds from the LOTUS database was screened using an e-pharmacophore model derived from the COX-2 crystal structure. Compounds that satisfied the pharmacophoric features were subjected to hierarchical molecular docking and were further evaluated through MMGBSA calculations, ADMET and AutoQSAR predictions. The selected compounds exhibited stronger binding affinities than the reference ligand (− 6.424 kcal/mol), with docking scores ranging from − 10.081 to − 8.348 kcal/mol. LTS0049922 showed the most favorable MMGBSA binding energy (− 54.44 kcal/mol), indicating strong and stable interaction within the COX-2 catalytic pocket. Interaction analysis revealed key hydrogen bonding with critical residues such as SER530, TYR385, ARG120, and TYR355. ADMET evaluation indicated favorable ADME and acceptable toxicity profiles for the lead compounds. AutoQSAR prediction identified LTS0025171 and LTS0049922 as the compound with the highest predicted inhibitory activity (6.879 and 5.925 respectively), surpassing the reference ligand (4.983). The integrated computational approach successfully identified promising natural compounds from the LOTUS database with potential inhibitory activity against human COX-2. In particular, LTS0025171 and LTS0049922 demonstrated strong binding affinity, favorable ADMET properties, and promising predicted biological activity. These compounds show potential lead scaffolds for the development of novel anti-inflammatory agents, although further experimental validation through in vitro and in vivo studies is required.