{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T23:09:34Z","timestamp":1772752174301,"version":"3.50.1"},"reference-count":92,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T00:00:00Z","timestamp":1589414400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001870","name":"Fundacja na rzecz Nauki Polskiej","doi-asserted-by":"publisher","award":["MAB\/3\/2017"],"award-info":[{"award-number":["MAB\/3\/2017"]}],"id":[{"id":"10.13039\/501100001870","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>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 \u201cup\u201d and \u201cdown\u201d state. In addition, the trimer cavity may function as a \u201cbouncing spring\u201d 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.<\/jats:p>","DOI":"10.3390\/jcm9051473","type":"journal-article","created":{"date-parts":[[2020,5,14]],"date-time":"2020-05-14T10:27:19Z","timestamp":1589452039000},"page":"1473","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":64,"title":["Highly Conserved Homotrimer Cavity Formed by the SARS-CoV-2 Spike Glycoprotein: A Novel Binding Site"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7757-6962","authenticated-orcid":false,"given":"Umesh","family":"Kalathiya","sequence":"first","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9132-8620","authenticated-orcid":false,"given":"Monikaben","family":"Padariya","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5673-8440","authenticated-orcid":false,"given":"Marcos","family":"Mayordomo","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4858-9312","authenticated-orcid":false,"given":"Ma\u0142gorzata","family":"Lisowska","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Nicholson","sequence":"additional","affiliation":[{"name":"Sharp Life Science (EU) Limited, Oxford Science Park, Edmund Halley Rd, Oxford OX4 4GB, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashita","family":"Singh","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6795-7515","authenticated-orcid":false,"given":"Maciej","family":"Baginski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Technology and Biochemistry, Faculty of Chemistry, Gdansk University of Technology, Narutowicza St 11\/12, 80-233 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robin","family":"Fahraeus","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neil","family":"Carragher","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0728-7169","authenticated-orcid":false,"given":"Kathryn","family":"Ball","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juergen","family":"Haas","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7308-4140","authenticated-orcid":false,"given":"Alison","family":"Daniels","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ted R.","family":"Hupp","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"},{"name":"Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier Antonio","family":"Alfaro","sequence":"additional","affiliation":[{"name":"International Centre for Cancer Vaccine Science, University of Gdansk, Wita Stwosza 63, 80-308 Gdansk, Poland"},{"name":"Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, Scotland EH4 2XR, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.tim.2013.05.005","article-title":"Interspecies transmission and emergence of novel viruses: Lessons from bats and birds","volume":"21","author":"Chan","year":"2013","journal-title":"Trends Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"660","DOI":"10.1128\/CMR.00023-07","article-title":"Severe acute respiratory syndrome coronavirus as an agent of emerging and reemerging infection","volume":"20","author":"Cheng","year":"2007","journal-title":"Clin. 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