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A Drug Repurposing Approach for Antimalarials Interfering with SARS-CoV-2 Spike Protein Receptor Binding Domain (RBD) and Human Angiotensin-Converting Enzyme 2 (ACE2).
Coghi, Paolo; Yang, Li Jun; Ng, Jerome P L; Haynes, Richard K; Memo, Maurizio; Gianoncelli, Alessandra; Wong, Vincent Kam Wai; Ribaudo, Giovanni.
  • Coghi P; School of Pharmacy, Macau University of Science and Technology, Taipa 999078, China.
  • Yang LJ; Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa 999078, China.
  • Ng JPL; Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa 999078, China.
  • Haynes RK; Center of Excellence for Pharmaceutical Sciences, Faculty of Health Sciences, North-West University Potchefstroom, Potchefstroom 2531, South Africa.
  • Memo M; Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
  • Gianoncelli A; Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
  • Wong VKW; Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa 999078, China.
  • Ribaudo G; Department of Molecular and Translational Medicine, University of Brescia, 25121 Brescia, Italy.
Pharmaceuticals (Basel) ; 14(10)2021 Sep 23.
Article in English | MEDLINE | ID: covidwho-1438690
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.
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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2021 Document Type: Article Affiliation country: Ph14100954

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Full text: Available Collection: International databases Database: MEDLINE Language: English Year: 2021 Document Type: Article Affiliation country: Ph14100954