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Open AccessArticle

Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site

1
International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland
2
Sharp Life Science (EU) Limited, Oxford Science Park, Edmund Halley Rd, Oxford OX4 4GB, UK
3
Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11/12, 80-233 Gdansk, Poland
4
Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK
5
Department of Infectious Disease, Edinburgh, Scotland EH4 2XR, UK
*
Authors to whom correspondence should be addressed.
J. Clin. Med. 2020, 9(5), 1473; https://doi.org/10.3390/jcm9051473
Received: 22 April 2020 / Revised: 8 May 2020 / Accepted: 12 May 2020 / Published: 14 May 2020
(This article belongs to the Section Infectious Diseases)
An important stage in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) life cycle is the binding of the spike (S) protein to the angiotensin converting enzyme-2 (ACE2) host cell receptor. Therefore, to explore conserved features in spike protein dynamics and to identify potentially novel regions for drugging, we measured spike protein variability derived from 791 viral genomes and studied its properties by molecular dynamics (MD) simulation. The findings indicated that S2 subunit (heptad-repeat 1 (HR1), central helix (CH), and connector domain (CD) domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the receptor binding domain (RBD) domain, which is typically targeted in drug discovery programs, exhibits more sequence variability and flexibility. Interpretations from MD simulations suggest that the monomer form of spike protein is in constant motion showing transitions between an “up” and “down” state. In addition, the trimer cavity may function as a “bouncing spring” that may facilitate the homotrimer spike protein interactions with the ACE2 receptor. The feasibility of the trimer cavity as a potential drug target was examined by structure based virtual screening. Several hits were identified that have already been validated or suggested to inhibit the SARS-CoV-2 virus in published cell models. In particular, the data suggest an action mechanism for molecules including Chitosan and macrolides such as the mTOR (mammalian target of Rapamycin) pathway inhibitor Rapamycin. These findings identify a novel small molecule binding-site formed by the spike protein oligomer, that might assist in future drug discovery programs aimed at targeting the coronavirus (CoV) family of viruses. View Full-Text
Keywords: SARS-CoV-2; coronavirus disease 2019 (COVID-19); spike glycoprotein; variability; molecular docking; molecular dynamics; inhibitors; trimer cavity; binding site SARS-CoV-2; coronavirus disease 2019 (COVID-19); spike glycoprotein; variability; molecular docking; molecular dynamics; inhibitors; trimer cavity; binding site
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Kalathiya, U.; Padariya, M.; Mayordomo, M.; Lisowska, M.; Nicholson, J.; Singh, A.; Baginski, M.; Fahraeus, R.; Carragher, N.; Ball, K.; Haas, J.; Daniels, A.; Hupp, T.R.; Alfaro, J.A. Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site. J. Clin. Med. 2020, 9, 1473.

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