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Direct Observation of Protonation State Modulation in SARS-CoV-2 Main Protease upon Inhibitor Binding with Neutron Crystallography.
Kneller, Daniel W; Phillips, Gwyndalyn; Weiss, Kevin L; Zhang, Qiu; Coates, Leighton; Kovalevsky, Andrey.
  • Kneller DW; Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States.
  • Phillips G; National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States.
  • Weiss KL; Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States.
  • Zhang Q; National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States.
  • Coates L; Neutron Scattering Division, Oak Ridge National Laboratory, 1 Bethel Valley Road, Oak Ridge, Tennessee 37831, United States.
  • Kovalevsky A; National Virtual Biotechnology Laboratory, US Department of Energy, Washington, D.C. 20585, United States.
J Med Chem ; 64(8): 4991-5000, 2021 04 22.
Article in English | MEDLINE | ID: covidwho-1574766
Semantic information from SemMedBD (by NLM)
1. Peptide Hydrolases INTERACTS_WITH Inhibitor
Subject
Peptide Hydrolases
Predicate
INTERACTS_WITH
Object
Inhibitor
2. Virus CAUSES COVID-19
Subject
Virus
Predicate
CAUSES
Object
COVID-19
3. Peptide Hydrolases INTERACTS_WITH Inhibitor
Subject
Peptide Hydrolases
Predicate
INTERACTS_WITH
Object
Inhibitor
4. Virus CAUSES COVID-19
Subject
Virus
Predicate
CAUSES
Object
COVID-19
ABSTRACT
The main protease (3CL Mpro) from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is an essential enzyme for viral replication with no human counterpart, making it an attractive drug target. To date, no small-molecule clinical drugs are available that specifically inhibit SARS-CoV-2 Mpro. To aid rational drug design, we determined a neutron structure of Mpro in complex with the α-ketoamide inhibitor telaprevir at near-physiological (22 °C) temperature. We directly observed protonation states in the inhibitor complex and compared them with those in the ligand-free Mpro, revealing modulation of the active-site protonation states upon telaprevir binding. We suggest that binding of other α-ketoamide covalent inhibitors can lead to the same protonation state changes in the Mpro active site. Thus, by studying the protonation state changes induced by inhibitors, we provide crucial insights to help guide rational drug design, allowing precise tailoring of inhibitors to manipulate the electrostatic environment of SARS-CoV-2 Mpro.
Subject(s)

Full text: Available Collection: International databases Database: MEDLINE Main subject: Oligopeptides / Coronavirus 3C Proteases Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c00058

Full text: Available Collection: International databases Database: MEDLINE Main subject: Oligopeptides / Coronavirus 3C Proteases Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c00058