Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3. SLAS Discov 2020 Dec;25(10):1162-1170
Date
09/29/2020Pubmed ID
32981460Pubmed Central ID
PMC7684785DOI
10.1177/2472555220960428Scopus ID
2-s2.0-85091680237 (requires institutional sign-in at Scopus site) 27 CitationsAbstract
Small molecules that bind the SARS-CoV-2 nonstructural protein 3 Mac1 domain in place of ADP-ribose could be useful as molecular probes or scaffolds for COVID-19 antiviral drug discovery because Mac1 has been linked to the ability of coronaviruses to evade cellular detection. A high-throughput assay based on differential scanning fluorimetry (DSF) was therefore optimized and used to identify possible Mac1 ligands in small libraries of drugs and drug-like compounds. Numerous promising compounds included nucleotides, steroids, β-lactams, and benzimidazoles. The main drawback to this approach was that a high percentage of compounds in some libraries were found to influence the observed Mac1 melting temperature. To prioritize DSF screening hits, the shapes of the observed melting curves and initial assay fluorescence were examined, and the results were compared with virtual screens performed using AutoDock Vina. The molecular basis for alternate ligand binding was also examined by determining a structure of one of the hits, cyclic adenosine monophosphate, with atomic resolution.
Author List
Virdi RS, Bavisotto RV, Hopper NC, Vuksanovic N, Melkonian TR, Silvaggi NR, Frick DNAuthor
David N. Frick PhD Associate Professor in the Chimistry & Biochemistry department at University of Wisconsin - MilwaukeeMESH terms used to index this publication - Major topics in bold
Antiviral AgentsBinding Sites
Cyclic AMP
High-Throughput Screening Assays
Ligands
Models, Molecular
Molecular Docking Simulation
Protein Conformation
Protein Domains
