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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.
Insights
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.
Abstract:
Coronavirus disease 2019 continues to pose global health challenges, with the pandemic significantly burdening several economies, healthcare systems, and the social lives of individuals. Furthermore, new cases continue to be reported, underscoring the need for therapeutic strategies targeting conserved regions and host-virus 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-virus interactions.
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