Sirtuins are nicotinamide adenine dinucleotide (NAD+)-dependent class III histone deacetylases that have been linked to the pathogenesis of numerous diseases such as HIV, metabolic disorders, neurodegeneration (including Alzheimer’s disease and Parkinson’s disease) and cancer. Recently, virtual screening for the identification of sirtuin inhibitors and modulators has received great interest. Docking of the virtual pan-African natural products library (p-ANAPL), followed bycareful hit selection and in vitro testing, resulted in the identification of inhibitors of sirtuin 1, 2 and 3 (sirt1-3). Two bichalcones; rhuschalcone IV (PubChem CID: 5472699) and a rhuschalcone I analogue, previously isolated from Rhus pyroides Burch (Anacardiaceae), a medicinal plant which is widely distributed in Eastern Botswana, were found to be sirtuin inhibitors. The two bichalcones were shown to be active in the in vitro assay, with rhuschalcone I showing the best activity against sirt1, having an IC50 = 40.8 µM. Based on the docking experiments, suggestions for improving the biological activities of the newly identified hit compounds have been provided, including testing the O- and C-C linked bichalcones (e.g. littorachalcone, verbenachalcone and rhuschalcones II, III, V and VI). Although the active rhuschalcones have been synthesized and known to possess other biological activities, it is yet unclear if their cytotoxicities are related to their abilities to inhibit sirtuins. However, natural product libraries like the p-ANAPL and the newly developed NANPDB libraries continue to be good starting points for the search of novel modulators of sirtuins with novel natural product scaffolds from African medicinal plants.

Identification of bichalcones as natural product sirtuin inhibitors by virtual screening and in vitro testing

256th National Meeting (2018)

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