Preprint Article Version 1 This version is not peer-reviewed

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

Version 1 : Received: 22 April 2020 / Approved: 24 April 2020 / Online: 24 April 2020 (11:42:01 CEST)

A peer-reviewed article of this Preprint also exists.

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. 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.

Journal reference: J. Clin. Med. 2020, 9, 1473
DOI: 10.3390/jcm9051473

Abstract

An important stage in SARS-CoV-2 life cycle is the fusion of spike(S) protein with the ACE2 host-cell receptor. Therefore, to explore conserved features in S protein dynamics and to identify potentially novel regions for drugging, we measured variability derived from 791 viral genomes and studied its properties by MD simulation. The findings indicated that S2 subunit (HR1, CH, and CD domains) showed low variability, low fluctuations in MD, and displayed a trimer cavity. By contrast, the RBD domain, which is typically targeted in drug discovery programmes, exhibits more sequence variability and flexibility. Interpretations from MD suggest that the monomer is in constant motion showing transitions up-to-down state, and the trimer cavity may function as a 'bouncing spring' that may facilitates S protein interactions with ACE2. Feasibility of trimer cavity for potential drug target was examined by SBVS screening. Several hits that have already been validated or suggested to inhibit the SARS-CoV-2 virus in cell systems were identified; in particular, the data suggest an action mechanism for such molecules including Chitosan and macrolide types. These findings identify a novel binding-site formed by the S protein, that might assist in future drug discovery programmes aimed at targeting the CoV family of viruses.

Subject Areas

SARS-CoV-2; COVID-19; spike glycoprotein; variability; molecular docking; molecular dynamics; inhibitors

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