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

Abstract

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 C₂₈ 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

Keywords:

• Athenaea velutina
• molecular dynamics
• molecular docking
• COVID-19
• withanolides
• M^pro

Acknowledgments

The authors thank High-Performance Computing Center (NPAD) at the Federal University of Rio Grande do Norte (UFRN) and the National High-Performance Processing Center of the Federal University of Ceará (UFC) for providing computational resources.

Disclosure statement

The authors declare no competing or financial interest.

Ethical statement

This study does not require ethics approval.

Additional information

Funding

This work was supported by the Instituto Nacional de Ciência e Tecnologia - INCT BioNat under Grant N°. 465637/2014-0; Conselho Nacional de Desenvolvimento Científico e Tecnológico—CNPq under Grant N°. 420454/2016-0, N°. 10183/2020-0, and N°. 140562/2019-2.