Discovery of bile acid derivatives as potent ACE2 activators by virtual screening and essential dynamics
- Fiorillo, Bianca ORCID Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Marchianò, Silvia ORCID Department of Medicine and Surgery, Università di Perugia School of Medicine, Perugia, Italy
- Moraca, Federica Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Sepe, Valentina Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Carino, Adriana ORCID Department of Medicine and Surgery, Università di Perugia School of Medicine, Perugia, Italy
- Rapacciuolo, Pasquale ORCID Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Biagioli, Michele ORCID Department of Medicine and Surgery, Università di Perugia School of Medicine, Perugia, Italy
- Limongelli, Vittorio ORCID Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy - Euler Institute (EUL), Università della Svizzera italiana, Switzerland
- Zampella, Angela Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Catalanotti, Bruno ORCID Department of Pharmacy, Università di Napoli “Federico II”, Napoli, Italy
- Fiorucci, Stefano ORCID Department of Medicine and Surgery, Università di Perugia School of Medicine, Perugia, Italy
- 2021
Published in:
- Journal of chemical information and modeling. - 2021, vol. 62, no. 1, p. 196–209
English
The angiotensin-converting enzyme II (ACE2) is a key molecular player in the regulation of vessel contraction, inflammation, and reduction of oxidative stress. In addition, ACE2 has assumed a prominent role in the fight against the COVID-19 pandemic-causing virus SARS-CoV-2, as it is the very first receptor in the host of the viral spike protein. The binding of the spike protein to ACE2 triggers a cascade of events that eventually leads the virus to enter the host cell and initiate its life cycle. At the same time, SARS-CoV-2 infection downregulates ACE2 expression especially in the lung, altering the biochemical signals regulated by the enzyme and contributing to the poor clinical prognosis characterizing the late stage of the COVID-19 disease. Despite its important biological role, a very limited number of ACE2 activators are known. Here, using a combined in silico and experimental approach, we show that ursodeoxycholic acid (UDCA) derivatives work as ACE2 activators. In detail, we have identified two potent ACE2 ligands, BAR107 and BAR708, through a docking virtual screening campaign and elucidated their mechanism of action from essential dynamics of the enzyme observed during microsecond molecular dynamics calculations. The in silico results were confirmed by in vitro pharmacological assays with the newly identified compounds showing ACE2 activity comparable to that of DIZE, the most potent ACE2 activator known so far. Our work provides structural insight into ACE2/ligand-binding interaction useful for the design of compounds with therapeutic potential against SARS-CoV-2 infection, inflammation, and other ACE2-related diseases
- Collections
- Language
-
- English
- Classification
- Medicine
- License
- CC BY
- Open access status
- hybrid
- Identifiers
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- DOI 10.1021/acs.jcim.1c01126
- ARK ark:/12658/srd1328294
- Persistent URL
- https://n2t.net/ark:/12658/srd1328294
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