Discovery of Drug-Like Ligands for the Mac1 Domain of SARS-CoV-2 Nsp3
| Autor: | Nemanja Vuksanovic, Rajdeep S Virdi, Trevor R Melkonian, Robert Bavisotto, Nicholas Hopper, Nicholas R. Silvaggi, David N. Frick |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Models
Molecular Protein Conformation coronavirus Coronavirus Papain-Like Proteases antiviral drug target macrodomain Trifluoperazine Ligands medicine.disease_cause 01 natural sciences Biochemistry Analytical Chemistry chemistry.chemical_compound Cyclic AMP Nucleotide Coronavirus media_common chemistry.chemical_classification 0303 health sciences Small molecule Molecular Docking Simulation Molecular Medicine Molecular probe medicine.drug Biotechnology Drug medicine.drug_class media_common.quotation_subject Rabeprazole Antiviral Agents Fluorescence spectroscopy Article 03 medical and health sciences Protein Domains medicine Cyclic adenosine monophosphate 030304 developmental biology Binding Sites Cefatrizine SARS-CoV-2 COVID-19 Isothermal titration calorimetry Combinatorial chemistry High-Throughput Screening Assays 0104 chemical sciences 010404 medicinal & biomolecular chemistry chemistry Antiviral drug thermal shift |
| Zdroj: | Slas Discovery bioRxiv |
| ISSN: | 2472-5560 2472-5552 |
| Popis: | The Mac1 domain of the multifunctional SARS-CoV-2 non-structural protein 3 (nsp3) is a potential COVID-19 drug target because it is suspected to enhance the ability of the virus to evade the human immune system. The SARS-CoV-2 Mac1 domain binds ADP-ribose and proteins harboring this important post-translational modification. Small molecules that bind the Mac1 domain in place of ADP-ribose might therefore be useful as molecular probes or scaffolds for antiviral drug discovery. Two high throughput screens were used here to identify such ligands in small libraries of drugs and drug-like compounds. The first screen used differential scanning fluorimetry (DSF, aka the thermal shift or ThermoFluor assay) to examine the melting temperature of SARS-CoV-2 Mac1 domain in the presence of various compounds. In the second screen, various high-resolution SARS-CoV-2 Mac1 structures were used with Autodock VINA to identify potential ligands. Numerous hit compounds were either steroids (estradiol valerate & flunisolide), beta-lactams (cefaclor & cefatrizine), or benzimidazoles (telmisartan, rabeprazole, omeprazole, & esomeprazole). Isothermal titration calorimetry was used to confirm that rabeprazole, omeprazole, and compounds in other chemical classes, such as irinotecan, nifedipine, trifluoperazine, bind SARS-CoV-2 Mac1 with an affinity similar to ADP-ribose. |
| Databáze: | OpenAIRE |
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