A drug repurposing approach for antimalarials interfering with SARS-COV-2 spike protein receptor binding domain (RBD) and human angiotensin-converting enzyme 2 (ACE2)

Paolo Coghi, Li Jun Yang, Jerome P.L. Ng, Richard K. Haynes, Maurizio Memo, Alessandra Gianoncelli, Vincent Kam Wai Wong, Giovanni Ribaudo

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)
34 Downloads (Pure)

Abstract

Host cell invasion by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is mediated by the interaction of the viral spike protein (S) with human angiotensin-converting enzyme 2 (ACE2) through the receptor-binding domain (RBD). In this work, computational and experimental techniques were combined to screen antimalarial compounds from different chemical classes, with the aim of identifying small molecules interfering with the RBD-ACE2 interaction and, consequently, with cell invasion. Docking studies showed that the compounds interfere with the same region of the RBD, but different interaction patterns were noted for ACE2. Virtual screening indicated pyronaridine as the most promising RBD and ACE2 ligand, and molecular dynamics simulations confirmed the stability of the predicted complex with the RBD. Bio-layer interferometry showed that artemisone and methylene blue have a strong binding affinity for RBD (KD = 0.363 and 0.226 µM). Pyronaridine also binds RBD and ACE2 in vitro (KD = 56.8 and 51.3 µM). Overall, these three compounds inhibit the binding of RBD to ACE2 in the µM range, supporting the in silico data.

Original languageEnglish
Article number954
Number of pages13
JournalPharmaceuticals
Volume14
Issue number10
Early online date23 Sept 2021
DOIs
Publication statusPublished - Oct 2021

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