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In-Depth Molecular Dynamics Simulations Reveal Ligand-Induced Modulations of the HSPA8-SARS-CoV-2 Spike Protein
Liberty T Navhaya1, Mokgerwa Z Monama1, Thabe M Matsebatlela1
1Department of Biochemistry, Microbiology, and Biotechnology, University of Limpopo, Turfloop Campus, Sovenga 7270, South Africa.
International Journal of Molecular Sciences
|May 27, 2026
Summary
Two small molecules were investigated for their potential to disrupt the interaction between heat shock protein HSPA8 and the SARS-CoV-2 spike protein. NSC36398 shows promise in destabilizing this host-virus complex, offering a new therapeutic strategy.
Area of Science:
- Molecular biology
- Biophysics
- Drug discovery
Background:
- Coronavirus disease 2019 (COVID-19) presents ongoing global health and economic challenges.
- Therapeutic strategies targeting conserved host-virus interactions are crucial for managing SARS-CoV-2.
- Heat shock 70 kDa protein 8 (HSPA8) is implicated in the SARS-CoV-2 lifecycle via its interaction with the viral spike glycoprotein.
Purpose of the Study:
- To investigate the molecular mechanisms by which small molecules NSC36398 and NSC281245 affect the HSPA8-SARS-CoV-2 spike protein interaction.
- To evaluate the potential of these molecules as therapeutic leads for COVID-19.
Main Methods:
- All-atom molecular dynamics (MD) simulations were employed to analyze the dynamic behavior of the HSPA8-spike protein complex.
- Binding-free-energy calculations were performed to quantify the interaction strength of the small molecules.
- Post-simulation analyses refined docking predictions and elucidated molecular interactions.
Main Results:
- NSC281245 demonstrated tight binding to the HSPA8-spike protein complex with minimal disruption at the interaction interface.
- NSC36398 induced domain-level destabilization effects, suggesting allosteric modulation, while maintaining stable polar contacts.
- These findings refine previous docking predictions and highlight distinct binding mechanisms.
Conclusions:
- NSC36398 shows significant potential as a modulator for disrupting the HSPA8-spike protein complex.
- This molecule may serve as a structural lead for developing novel inhibitors targeting host-virus interactions in SARS-CoV-2.
- Targeting host-virus interactions offers a promising avenue for next-generation antiviral therapies.
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