Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets

Area of Science:

• Molecular Biology
• Virology
• Drug Discovery

Background:

• Ivermectin (IVM), an FDA-approved drug, exhibits broad-spectrum antiviral properties.
• IVM interferes with the importin-α/β1 complex, crucial for viral protein translocation and replication.
• The precise molecular mechanisms of IVM's inhibition of SARS-CoV-2 remain incompletely understood.

Purpose of the Study:

• To elucidate the energetic and structural basis of Ivermectin's inhibition of SARS-CoV-2.
• To investigate IVM's interaction with importin-α and five key SARS-CoV-2 targets.
• To identify the primary molecular targets responsible for IVM's in vitro antiviral activity.

Main Methods:

• Molecular docking simulations were employed to predict binding interactions.
• Molecular Dynamics (MD) simulations were used to analyze complex stability.
• Molecular Mechanics Generalized Born Surface Area (MMGBSA) calculations assessed binding affinities.

Main Results:

• Energetic and structural analyses identified the main protease 3CLpro as the primary target of IVM.
• Importin-α and Nsp9 were also identified as significant targets, showing similar binding affinities.
• IVM demonstrated the most favorable binding affinity towards dimeric 3CLpro.

Conclusions:

• The in vitro antiviral activity of Ivermectin against SARS-CoV-2 is attributed to its inhibitory effects on importin-α, Nsp9, and particularly dimeric 3CLpro.
• This study provides a detailed molecular understanding of Ivermectin's mechanism of action against SARS-CoV-2.
• Findings highlight dimeric 3CLpro as a key target for IVM's antiviral efficacy.