In silico identification of potential COX-2 inhibitors from sapelenins: molecular docking, molecular dynamics, MM-GBSA, DFT, and pharmacokinetic analysis
Cyrille Menye, Mathieu Jules Mbenga Tjegbe, Christophe Nkem, Baruch Amana Ateba, JOEL OJOGBANE ONOJA, Cyril Assongo Kenfack, Fidele Ntie‐Kang · In Silico Research in Biomedicine · 2026
Inflammation is a key component of the body's innate defense, but its dysregulation contributes to diseases such as rheumatoid arthritis and cardiovascular disorders. Cyclooxygenase‑2 (COX‑2) plays a central role in pain and inflammation by generating pro‑inflammatory prostaglandins, making it a validated target for anti‑inflammatory drug development. However, conventional nonsteroidal anti‑inflammatory drugs (NSAIDs) and selective COX‑2 inhibitors (coxibs) are associated with significant gastrointestinal and cardiovascular adverse effects, driving the search for safer alternatives. In this study, we investigated the anti‑inflammatory potential of fourteen sapelenins rare acyclic and tetracyclic triterpenes isolated from Entandrophragma cylindricum using an integrated in silico approach combining molecular docking, molecular dynamics (MD) simulations, MM‑GBSA binding free energy calculations, density functional theory (DFT), and pharmacokinetic (ADMET) predictions. Molecular docking and MM‑GBSA rescoring identified SAP J and SAP N as the most promising candidates, with binding affinities exceeding that of the co‑crystallized ligand rofecoxib. MD simulations (100 ns) demonstrated stable binding of both compounds within the COX‑2 active site, with RMSD and RMSF profiles indicating maintained interactions. MM‑GBSA calculations yielded ΔG_bind values of −72.33 kcal/mol (SAP J) and −53.22 kcal/mol (SAP N), compared to −46.26 kcal/mol for rofecoxib. SAP J and SAP N were predicted to be selective for COX-2, exhibiting reduced affinity toward COX-1. DFT analysis revealed that SAP J possesses a large HOMO‑LUMO gap (6.62 eV) and high chemical hardness, suggesting kinetic stability and reduced off‑target reactivity. Additionally, SAP N displayed acceptable drug-likeness and pharmacokinetic properties. Despite exceeding the recommended lipophilicity threshold and exhibiting low predicted gastrointestinal absorption, SAP J retains considerable therapeutic potential, and structural optimization may help overcome these pharmacokinetic limitations. These findings identify SAP J and SAP N as promising lead compounds for COX‑2 inhibition. Their favorable binding, stability, electronic properties, and preliminary safety profiles warrant further experimental validation through enzymatic assays and in vivo studies.