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Zinc thiotropolone combinations as inhibitors of the SARS-CoV-2 main protease.
DeLaney, Christopher; Sheng, Yan; Pectol, D Chase; Vantansever, Erol; Zhang, Hanyuan; Bhuvanesh, Nattamai; Salas, Isaiah; Liu, Wenshe R; Fierke, Carol F; Darensbourg, Marcetta Y.
  • DeLaney C; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Sheng Y; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Pectol DC; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Vantansever E; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Zhang H; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Bhuvanesh N; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Salas I; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Liu WR; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Fierke CF; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
  • Darensbourg MY; 3255 TAMU, College Station, TX, 77843, USA. marcetta@mail.chem.tamu.edu.
Dalton Trans ; 50(35): 12226-12233, 2021 Sep 14.
Article in English | MEDLINE | ID: covidwho-1358359
ABSTRACT
Numerous organic molecules are known to inhibit the main protease of SARS-CoV-2, (SC2Mpro), a key component in viral replication of the 2019 novel coronavirus. We explore the hypothesis that zinc ions, long used as a medicinal supplement and known to support immune function, bind to the SC2Mpro enzyme in combination with lipophilic tropolone and thiotropolone ligands, L, block substrate docking, and inhibit function. This study combines synthetic inorganic chemistry, in vitro protease activity assays, and computational modeling. While the ligands themselves have half maximal inhibition concentrations, IC50, for SC2Mpro in the 8-34 µM range, the IC50 values are ca. 100 nM for Zn(NO3)2 which are further enhanced in Zn-L combinations (59-97 nM). Isolation of the Zn(L)2 binary complexes and characterization of their ability to undergo ligand displacement is the basis for computational modeling of the chemical features of the enzyme inhibition. Blind docking onto the SC2Mpro enzyme surface using a modified Autodock4 protocol found preferential binding into the active site pocket. Such Zn-L combinations orient so as to permit dative bonding of Zn(L)+ to basic active site residues.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Tropolone / Zinc / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Dalton Trans Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: D1dt02499j

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Protease Inhibitors / Tropolone / Zinc / Coronavirus 3C Proteases / SARS-CoV-2 / COVID-19 Limits: Humans Language: English Journal: Dalton Trans Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: D1dt02499j