Fragment-based design of SARS-CoV-2 Mpro inhibitors

Area of Science:

• Medicinal Chemistry
• Computational Drug Design
• Virology

Background:

• The COVID-19 pandemic, caused by SARS-CoV-2, has resulted in millions of deaths globally.
• The viral main protease (Mpro) is crucial for SARS-CoV-2 replication, making it a key target for antiviral drug development.

Purpose of the Study:

• To design and identify novel Mpro inhibitors for COVID-19 treatment using a fragment linking strategy.
• To evaluate the potential of newly designed molecules as COVID-19 therapeutics.

Main Methods:

• Screening of 293,451 fragments for binding affinity to Mpro.
• Utilizing Schrödinger software for fragment joining to generate 100 new molecules.
• Assessing Mpro binding affinity, ADMET properties, and drug-likeness of the generated molecules.
• Conducting molecular dynamics simulations using GROMACS for stability analysis of top compounds.

Main Results:

• Identified 13 lead molecules with potential Mpro inhibitory activity.
• Selected the top 6 compounds for molecular dynamics studies to assess ligand-receptor complex stability.
• The designed molecules demonstrated potential for further development in COVID-19 drug discovery.

Conclusions:

• The fragment linking approach successfully generated novel Mpro inhibitors.
• The identified compounds warrant further investigation as potential antiviral agents against SARS-CoV-2.
• This study contributes to the ongoing efforts to find effective treatments for COVID-19.