Withanolides of Athenaea velutina with potential inhibitory properties against SARS coronavirus main protease (mpro): molecular modeling studies

Since the global COVID-19 pandemic began, the scientific community has dedicated efforts to finding effective antiviral drugs to treat or minimize the effects caused by the SARS-CoV-2 coronavirus. Some targets can act as inhibitor substrates, highlighting the Main Protease (M-pro), which plays an essential role in the translation and transcription of the virus cycle. Withanolides, a class of natural C-28 steroidal lactones, are compounds of interest as possible inhibitors of M-pro and other critical targets of the virus, such as papain-like protease. In this study, the isolation of a new withanolide (1), along with the known 27-deoxywithaferin A (2) and 27-deoxy-2,3-dihydrowithaferin A (3), from the leaves of Athenaea velutina (Solanaceae) is described. Their structures were determined using spectroscopic and spectrometric methods (NMR, IR, HRESIMS). Moreover, the interaction and the stability of withanolides 1-3 and withanolide D (4), previously isolated of Acnistus arborescens, against the M-pro target through molecular docking, molecular dynamics, and binding free energy simulations were analyzed. The molecular dynamics results indicated that the complexes formed by the molecular docking simulations between the M-pro target with each of the withanolides 1-4 exhibited good stability during the simulations due to a slight change in the structure of complexes. The binding free energy results suggested that withanolide (1) can be a natural candidate against COVID-19 disease. Communicated by Ramaswamy H. Sarma