Discovery of Aspxanthones A-I with SIRT1 agonist activity from Aspergillus sp. TJ507.

Nine previously undescribed prenylated xanthones, aspxanthones A-I (1-9), were isolated and characterized from the endophytic fungus Aspergillus sp. TJ507. Their structures were established through comprehensive spectroscopic analyses, single-crystal X-ray diffraction, and DP4+ probability analysis. Compounds 1, 2, and 4 exhibited modest in vitro SIRT1 activating effects, with EC50 values ranging from 9.3 to 13.7 μM. The positive control resveratrol yielded an EC50 of 2.4 ± 0.4 μM under identical assay conditions. Molecular docking was conducted with resveratrol as a reference ligand, which revealed obvious differences in binding modes between resveratrol and the tested xanthones. To further clarify their dynamic binding behaviors, molecular dynamics simulations, free-energy landscape analysis, and MM/GBSA calculations were carried out on these active compounds. Among them, compound 4 displayed the most stable simulated binding profile and the most favorable estimated binding free energy among the three complexes, broadly consistent with the experimental activity ranking. In contrast, compound 2 exhibited higher conformational flexibility throughout the simulation, indicating a distinct binding mode. This study expands the chemical diversity of fungal-derived xanthones and provides valuable templates for the design and development of potential SIRT1 activators.