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Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study
Meghdad Razizadeh1, Mehdi Nikfar1, Yaling Liu2
1Department of Mechanical Engineering and Mechanics, Bethlehem, Pennsylvania.
Abstract:
The ongoing coronavirus disease 19 (COVID-19) pandemic has infected millions of people, claimed hundreds of thousands of lives, and made a worldwide health emergency. Understanding the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mechanism of infection is crucial in the development of potential therapeutics and vaccines. The infection process is triggered by direct binding of the SARS-CoV-2 receptor-binding domain (RBD) to the host-cell receptor angiotensin-converting enzyme 2 (ACE2). Many efforts have been made to design or repurpose therapeutics to deactivate the RBD or ACE2 and prevent the initial binding. In addition to direct inhibition strategies, small chemical compounds might be able to interfere and destabilize the metastable, prefusion complex of ACE2-RBD. This approach can be employed to prevent the further progress of virus infection at its early stages. In this study, molecular docking was employed to analyze the binding of two chemical compounds, SSAA09E2 and Nilotinib, with the druggable pocket of the ACE2-RBD complex. The structural changes as a result of the interference with the ACE2-RBD complex were analyzed by molecular dynamics simulations. Results show that both Nilotinib and SSAA09E2 can induce significant conformational changes in the ACE2-RBD complex, intervene with the hydrogen bonds, and influence the flexibility of proteins. Moreover, essential dynamics analysis suggests that the presence of small molecules can trigger large-scale conformational changes that may destabilize the ACE2-RBD complex.
Insights
Two compounds, Nilotinib and SSAA09E2, were studied for their potential to disrupt the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein binding to host cells. These molecules may destabilize the ACE2-RBD complex, offering a novel therapeutic strategy against COVID-19.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- The COVID-19 pandemic necessitates understanding SARS-CoV-2 infection mechanisms for therapeutic development.
- Viral entry involves the SARS-CoV-2 receptor-binding domain (RBD) binding to the host ACE2 receptor.
- Direct inhibition strategies target RBD or ACE2, but destabilizing the ACE2-RBD complex is an alternative approach.
Purpose of the Study:
- To investigate the potential of small molecules to interfere with and destabilize the ACE2-RBD complex.
- To analyze the binding of SSAA09E2 and Nilotinib to the ACE2-RBD complex using molecular docking.
- To assess the structural and dynamic effects of these compounds on the ACE2-RBD complex via molecular dynamics simulations.
Main Methods:
- Molecular docking was used to predict the binding interactions of SSAA09E2 and Nilotinib with the ACE2-RBD complex.
- Molecular dynamics simulations were performed to analyze the conformational changes and stability of the complex upon compound binding.
- Essential dynamics analysis was employed to understand the large-scale motions induced by the small molecules.
Main Results:
- Both Nilotinib and SSAA09E2 demonstrated the ability to bind to the ACE2-RBD complex.
- The compounds induced significant conformational changes and altered protein flexibility within the ACE2-RBD complex.
- Interference with hydrogen bonds and potential destabilization of the ACE2-RBD complex were observed.
Conclusions:
- Small molecules like Nilotinib and SSAA09E2 can interfere with the ACE2-RBD interaction.
- These compounds may destabilize the ACE2-RBD complex, presenting a potential strategy for inhibiting SARS-CoV-2 entry.
- Further research into these compounds could lead to novel therapeutic interventions for COVID-19.
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