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Pharmacodynamic studies further reported that sesquiterpene lactones might exert therapeutic effects by inhibiting NF-ОєB and MAPK pathway activation 3, 4, 5, 6, 7, 8. Researches revealed that they could be used in medicines against inflammation, cancer, malaria, and viral and bacterial infection 1, 2. Sesquiterpene lactones are plant-derived bioactive constituents, which have subjected numerous studies.

At present, research institutions or companies are devoting themselves to discovery a class of bioactive compounds, their valuable target proteins and mechanisms of action against diseases. Recent studies have indicated that medicinal herbs have been gradually widely used despite insufficient information correlating with their mechanism of action. Such molecular mechanism may provide a better insight into the molecular development or modification for ubiquitin-related drugs. Our results successfully explained the mechanism of 1ОІ-hydroxy alantolactone covalently bonding with UbcH5s. More importantly, we have found that Cys85 of UbcH5c is more efficient to form a covalent bond with the ligand in comparison with UbcH5a and UbcH5b. Besides, Asp112 and Asn114 function as anchors to fix ligand, ensuring it steadily docked at catalytic site to complete covalent reaction. Intermediate and product of catalytic reaction are also certified to be stable. Molecular dynamics further demonstrates that 1ОІ-hydroxy alantolactone can steadily combine with UbcH5s. Results revealed that the structure of the catalytic site is stable, and 1ОІ-hydroxy alantolactone can dock at the catalytic site with correct conformation.

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The QM/MM methodology was used to calculate the free energy barrier of hydrogen transfer and formation of covalent bond between 15-position carbon of ligand and Cys85. Molecular dynamics was used to detect the stability of docking complexes of 1ОІ-hydroxy alantolactone and UbcH5s, the covalently bonded intermediates and the products. The electrostatic surface and charge distribution of ligand and proteins were analyzed by quantitative calculation. Docking method was then used to predict conformations of ligand docked at the catalytic site of UbcH5s.

Molecular dynamics was performed to detect the structural stability of the catalytic site. Here, we analyzed the structural specificity of the catalytic site of UbcH5s by comparing them with other E2 proteins. Recently, it has been found to target UbcH5s by covalently bonding with Cys85 specifically, but the exact molecular basis remains unclear. 1ОІ-hydroxy alantolactone, a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities.