Efficient discrimination of natural stereoisomers of chicoric acid, an HIV-1 integrase inhibitor

Plants from the Asteraceae family are known to contain a wide spectrum of phytochemicals with various nutraceutical properties. One important phytochemical, chicoric acid (CA), is reported to exist in plants, such as Sonchus oleraceus and Bidens pilosa, as stereoisomers. These CA molecules occur either as the naturally abundant RR-chicoric acid (RR-CA), or the less abundant RS-chicoric acid (RS-CA), also known as meso-chicoric acid. To date, little is known about the biological activity of RS-CA, but there is evidence of its anti-human immunodeficiency virus (HIV) properties. In this study, a reliable analytical method was developed to distinguish between the two stereoisomers detected in S. oleraceus and B. pilosa. For structure identification and characterization of CA molecules, liquid chromatography–mass spectrometry (LC-MS) was used in combination with ultraviolet radiation (UV)-induced geometrical isomerization, molecular dynamics (MD) simulations, and density functional theory (DFT) models. Optimized structures from DFT calculations were used for docking studies against the HIV-1 integrase enzyme. Different retention times on the reverse phase chromatograms revealed that the plants produce two different CA stereoisomers: S. oleraceus produced the RR-CA isomer, while B. pilosa produced the RS-CA isomer. DFT results demonstrated the RR-CA molecule was more stable than RS-CA due to the stabilizing force of intra-molecular hydrogen bonding. Differences in the HIV-1 integrase enzyme binding modes were observed, with the RR-CA being a more potent inhibitor than the RS-CA molecule. The results highlight the significance of plant metabolite structural complexity from both chemical and biological perspectives. Furthermore, the study demonstrates that induced-formation of geometrical isomers, in combination with the predictive ability of DFT models and the resolving power of the LC-MS, can be exploited to distinguish structurally closely related compounds, such as stereoisomers.