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Furthermore, new cases continue to be reported, underscoring the need for therapeutic strategies targeting conserved regions and host\u2013virus interactions. Building on earlier virtual screening for small molecules, all-atom molecular dynamics simulations and binding-free-energy calculations were performed to elucidate how the two previously identified small molecules (NSC36398 and NSC281245) may affect the dynamic behaviour of the interaction between heat shock 70 kDa protein 8 (HSPA8) and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein. Post-MD analyses refined prior docking predictions, where NSC281245 was found to bind tightly to the complex with limited perturbations at the HSPA8-spike protein interaction surface, whereas NSC36398 appeared to induce allosteric-like domain-level destabilisation effects while maintaining stable polar contacts with the protein. Our findings demonstrate the potential of NSC36398 as a promising modulator for disrupting the HSPA8-spike protein complex, which may serve as a structural lead for designing next-generation inhibitors of host\u2013virus interactions.<\/jats:p>","DOI":"10.3390\/ijms27104288","type":"journal-article","created":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T16:04:36Z","timestamp":1778601876000},"page":"4288","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In-Depth Molecular Dynamics Simulations Reveal Ligand-Induced Modulations of the HSPA8-SARS-CoV-2 Spike Protein Interaction"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1815-1272","authenticated-orcid":false,"given":"Liberty T.","family":"Navhaya","sequence":"first","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Biotechnology, University of Limpopo, Turfloop Campus, Sovenga 7270, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mokgerwa Z.","family":"Monama","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Biotechnology, University of Limpopo, Turfloop Campus, Sovenga 7270, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6506-4070","authenticated-orcid":false,"given":"Thabe M.","family":"Matsebatlela","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Microbiology, and Biotechnology, University of Limpopo, Turfloop Campus, Sovenga 7270, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7238-4619","authenticated-orcid":false,"given":"Xolani H.","family":"Makhoba","sequence":"additional","affiliation":[{"name":"Department of Life and Consumer Sciences, College of Agriculture and Environmental Sciences, University of South Africa (UNISA), Florida Campus, Roodepoort 1709, South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s12941-021-00438-7","article-title":"COVID-19: Breaking Down a Global Health Crisis","volume":"20","author":"Mallah","year":"2021","journal-title":"Ann. 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