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High-Throughput Screening and Quantum Mechanics for Identifying Potent Inhibitors Against Mac1 Domain of SARS-CoV-2
Abstract:
SARS-CoV-2 encodes the Mac1 domain within the large nonstructural protein 3 (Nsp3), which has an ADP-ribosylhydrolase activity conserved in other coronaviruses. The enzymatic activity of Mac1 makes it an essential virulence factor for the pathogenicity of coronavirus (CoV). They have a regulatory role in counteracting host-mediated antiviral ADP-ribosylation, which is unique part of host response towards viral infections. Mac1 shows highly conserved residues in the binding pocket for the mono and poly ADP-ribose. Therefore, SARS-CoV-2 Mac1 enzyme is considered as an ideal drug target and inhibitors developed against them can possess a broad antiviral activity against CoV. ADP-ribose-1 phosphate bound closed form of Mac1 domain is considered for screening with large database of ZINC. XP docking and QPLD provides strong potential lead compounds, that perfectly fits inside the binding pocket. Quantum mechanical studies expose that, substrate and leads have similar electron donor ability in the head regions, that allocates tight binding inside the substrate-binding pocket. Molecular dynamics study confirms the substrate and new lead molecules presence of electron donor and acceptor makes the interactions tight inside the binding pocket. Overall binding phenomenon shows both substrate and lead molecules are well-adopt to bind with similar binding mode inside the closed form of Mac1.
Insights
Researchers identified potential drug candidates targeting the SARS-CoV-2 Mac1 enzyme, a key virulence factor in coronaviruses. These inhibitors could offer broad antiviral activity against related viruses.
Area of Science:
- Virology
- Biochemistry
- Drug Discovery
Background:
- Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) utilizes the Mac1 domain within its nonstructural protein 3 (Nsp3).
- The Mac1 domain possesses ADP-ribosylhydrolase activity, crucial for coronavirus (CoV) pathogenicity and virulence.
- This enzyme counteracts host antiviral ADP-ribosylation, a unique host defense mechanism against viral infections.
Purpose of the Study:
- To identify potential drug targets within SARS-CoV-2.
- To screen for novel inhibitors of the SARS-CoV-2 Mac1 enzyme.
- To evaluate the broad-spectrum antiviral potential of Mac1 inhibitors against coronaviruses.
Main Methods:
- Computational screening of a large chemical database (ZINC) against the ADP-ribose-1 phosphate bound closed form of the Mac1 domain.
- XP docking and Quantum Polarized Ligand Docking (QPLD) for lead compound identification.
- Quantum mechanical studies and molecular dynamics simulations to analyze binding interactions.
Main Results:
- Identification of strong potential lead compounds that fit precisely within the Mac1 binding pocket.
- Quantum mechanical studies revealed similar electron donor abilities between substrates and lead compounds in key regions.
- Molecular dynamics confirmed tight binding interactions due to electron donor and acceptor properties of both substrate and lead molecules.
Conclusions:
- The SARS-CoV-2 Mac1 enzyme is a promising drug target due to conserved binding pocket residues.
- Identified lead compounds exhibit favorable binding characteristics, suggesting potential for broad-spectrum antiviral activity against coronaviruses.
- The binding mode of lead molecules closely mimics that of the natural substrate within the closed Mac1 domain.
