Symphoxanthone and Celibixanthone as ACE2 Inhibitors against SARS-CoV-2 Using Molecular Docking, MM GBSA and Molecular Dynamics Studies

Abstract

The COVID-19 pandemic posed an unprecedented global health challenge, leading to the rapid development of vaccines and antiviral drugs that substantially reduced disease-related mortality. Nevertheless, conventional synthetic drug discovery remains time-consuming and is often associated with adverse effects, prompting interest in alternative therapeutic strategies based on natural products. One viable antiviral approach involves inhibiting angiotensin-converting enzyme 2 (ACE2), the primary host receptor that mediates SARS-CoV-2 entry through interaction with the receptor-binding domain (RBD) of the viral spike protein. In this study, we aimed to identify potential phytochemical inhibitors of ACE2 that could serve as potential antiviral candidates against SARS-CoV-2. Molecular docking was performed using standard precision (SP) and extra precision (XP) protocols, with nelfinavir, hydroxychloroquine, nirmatrelvir, and Paxlovid employed as reference drugs approved by the United States Food and Drug Administration. The binding free energy was estimated using MM-GBSA calculations. The ACE2 structure was extracted from the ACE2-RBD complex (PDB ID: 6M0J) by removing the viral RBD before docking. The most promising ligand-receptor complexes were further evaluated through 100 ns molecular dynamics simulations. Structural stability and conformational behaviour were assessed using root-mean-square deviation (RMSD), root-mean-square fluctuation (RMSF), and radius of gyration (Rg) analyses. The results indicated that the phytochemicals NP#0158 (Symphoxanthone) and NP#0157 (Celibixanthone) exhibited favourable docking scores, binding free energies, and stable interaction profiles comparable to hydroxychloroquine. These findings suggest that Symphoxanthone and Celibixanthone may serve as promising natural-product-based ACE2 inhibitors and warrant further experimental validation as potential antiviral agents against SARS-CoV-2.