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Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease
Anuj Gahlawat1, Navneet Kumar1, Rajender Kumar2
1Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), S.A.S. Nagar 160062, Punjab, India.
Journal of Chemical Information and Modeling
|July 21, 2020
Summary
This study analyzed mutations in SARS-CoV-2 main protease (Mpro) and screened potential inhibitors. Findings reveal specific mutations impact the active site and identify promising drug scaffolds for COVID-19 treatment.
Area of Science:
- Biochemistry
- Structural Biology
- Drug Discovery
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates novel therapeutic strategies.
- The SARS-CoV-2 main protease (Mpro) is crucial for viral replication and a key drug target.
Purpose of the Study:
- To analyze the structural impact of Mpro mutations on the active site.
- To virtually screen for potential SARS-CoV-2 Mpro inhibitors from diverse compound libraries.
Main Methods:
- Comparative protein sequence and 3D structural analysis of Mpro active site mutations.
- Structure-based virtual screening of natural products, known protease inhibitors, and FDA-approved drugs.
- Molecular dynamics simulations to assess compound-active site interactions.
Main Results:
- Two mutations (Ser46 and Phe134) significantly altered the Mpro active site, affecting subpocket interactions and catalytic efficiency.
- Virtual screening identified 73 potential inhibitors with a combo score >2.0, belonging to eight structural scaffold classes.
- Screened compounds demonstrated favorable interactions within the Mpro active site, confirmed by molecular dynamics.
Conclusions:
- Specific Mpro mutations can modulate enzyme activity and substrate specificity.
- The study identified promising structural scaffolds for Mpro inhibition, offering a basis for rational drug design against SARS-CoV-2.
