Identification and characterization of novel RdRp and Nsp15 inhibitors for SARS-COV2 using computational approach

Area of Science:

• Computational drug discovery
• Virology
• Medicinal chemistry

Background:

• COVID-19, caused by SARS-CoV-2, is a global health emergency requiring new therapeutics.
• Targeting viral enzymes like RNA dependent RNA polymerase (RdRp) and Nsp15/EndoU is crucial for inhibiting viral replication.

Purpose of the Study:

• To identify potential drug repurposing candidates for COVID-19 treatment.
• To discover inhibitors for SARS-CoV-2 RNA dependent RNA polymerase (RdRp) and Nsp15/EndoU using computational methods.

Main Methods:

• Employed computer-aided drug repurposing campaigns to screen for inhibitors.
• Utilized molecular dynamics (MD) simulations to analyze the binding interactions of lead molecules with target enzymes.
• Focused on identifying compounds that mimic natural substrate interactions within the enzyme active sites.

Main Results:

• Identified Alectinib as a potential inhibitor for RdRp.
• Identified Naldemedine and Ergotamine as potential inhibitors for Nsp15.
• Observed that these lead molecules form stable interactions (hydrogen bonds, pi-type, hydrophobic) with key active site residues of the target enzymes.

Conclusions:

• Alectinib, Naldemedine, and Ergotamine are proposed as novel lead molecules for repurposing against COVID-19 targets.
• These compounds demonstrate molecular mimicry, interacting with essential catalytic residues.
• The identified inhibitors offer a promising starting point for developing more effective anti-SARS-CoV-2 therapeutics.