Exploiting the co-crystal ligands shape, features and structure-based approaches for identification of SARS-CoV-2...

Area of Science:

• Biochemistry
• Drug Discovery
• Computational Chemistry

Background:

• Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) utilizes the ACE2 receptor for host cell entry and relies on RNA-Dependent RNA Polymerase (RDRP) for replication.
• The viral Main protease (Mpro) is essential for processing viral polyproteins, making it a critical target for antiviral drug development.

Purpose of the Study:

• To identify novel small synthetic inhibitors targeting the SARS-CoV-2 Mpro through a hierarchical virtual screening approach.
• To evaluate the binding stability and affinity of potential Mpro inhibitors using molecular dynamics simulations.

Main Methods:

• Hierarchical virtual screening utilizing molecular shape and functional group features.
• Docking studies of screened compounds into the Mpro catalytic binding site.
• Molecular dynamics (MD) simulations and MM/GB(PB)SA binding free energy calculations for top-ranked compounds.

Main Results:

• A virtual screening workflow identified 29 common best hits from extensive databases.
• Five lead compounds demonstrated favorable structural stability and binding affinity with Mpro in MD simulations.
• The identified compounds serve as promising starting points for developing potent Mpro inhibitors.

Conclusions:

• The study successfully identified potential lead compounds for Mpro inhibition, offering new avenues for COVID-19 therapeutic strategies.
• These findings contribute to expanding the chemical space for designing effective antiviral agents against SARS-CoV-2.