Inhibitory effects of 190 compounds against SARS-CoV-2 M^{pr o} protein: Molecular docking interactions

Area of Science:

• Medicinal Chemistry
• Virology
• Drug Discovery

Background:

• COVID-19 remains a global health challenge, necessitating new antiviral strategies beyond vaccines and existing drugs.
• Emerging SARS-CoV-2 variants and limitations of current treatments underscore the need for novel therapeutic agents.
• The SARS-CoV-2 main protease (Mpro) is a critical target for antiviral drug development due to its essential role in viral replication.

Purpose of the Study:

• To screen a diverse library of natural and synthetic compounds for inhibitory activity against the SARS-CoV-2 main protease (Mpro).
• To identify novel chemical scaffolds with potential as antiviral leads against SARS-CoV-2.
• To investigate the binding interactions of active compounds with the Mpro active site through molecular docking.

Main Methods:

• In vitro screening of 190 compounds (27 natural, 163 synthetic) against purified SARS-CoV-2 Mpro.
• Determination of inhibitory constant (Ki) values for active compounds.
• Molecular docking studies using crystal structures of Mpro (PDB IDs: 5RG1, 5RG2, 5RG3).

Main Results:

• Twenty-five compounds demonstrated Mpro inhibitory activity, with Ki values ranging from 23.2 to 241 µM.
• A specific thiosemicarbazone derivative emerged as the most potent inhibitor identified in the screen.
• Molecular docking revealed key interactions, including hydrophobic, hydrogen bonding, and steric interactions, within the Mpro active site.

Conclusions:

• Thiosemicarbazone derivatives show promise as potential antiviral leads for developing new treatments against SARS-CoV-2.
• Further exploration and optimization of these compounds are warranted for therapeutic development.
• The study highlights the importance of rigorous evaluation to avoid false-positive results in drug screening.