Small molecule therapeutics to destabilize the ACE2-RBD complex: A molecular dynamics study.

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.