Unmasking an Allosteric Binding Site of the Papain-like Protease in SARS-CoV-2 : Molecular Dynamics Simulations of Corticosteroids
To date, mechanistic insights into many clinical drugs against COVID-19 remain unexplored. Dexamethasone, a corticosteroid, is one of them. While treating the entire corticosteroid database, including vitamins D2 and D3, with cutting-edge computational techniques, several intriguing results are unfolded. From the top-notch candidates, dexamethasone is likely to inhibit the viral main protease (Mpro), with vitamin D3 exhibiting multitarget [Mpro, papain-like protease (PLpro), and nucleocapsid protein (N-pro)] roles and ciclesonide's dynamic flipping disinterring a cryptic allosteric site in the PLpro enzyme. The results rationalize why these drugs improve the health of COVID-19 patients. Understanding an enzyme's secret binding site is essential to understanding how the enzyme works and how to inhibit its function. Ciclesonide's allosteric inhibition could not only jeopardize PLpro's catalytic role in polyprotein processing but also make it less vulnerable to the host body's defense machinery. Hotspot residues in the identified allosteric site could be considered for effective therapeutic designs against PLpro.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:14 |
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| Enthalten in: |
The journal of physical chemistry letters - 14(2023), 45 vom: 16. Nov., Seite 10278-10284 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Panda, Saroj Kumar [VerfasserIn] |
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| Links: |
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| Themen: |
7S5I7G3JQL |
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| Anmerkungen: |
Date Completed 17.11.2023 Date Revised 17.11.2023 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1021/acs.jpclett.3c01980 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM36434640X |
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| 100 | 1 | |a Panda, Saroj Kumar |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Unmasking an Allosteric Binding Site of the Papain-like Protease in SARS-CoV-2 |b Molecular Dynamics Simulations of Corticosteroids |
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| 500 | |a Date Revised 17.11.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a To date, mechanistic insights into many clinical drugs against COVID-19 remain unexplored. Dexamethasone, a corticosteroid, is one of them. While treating the entire corticosteroid database, including vitamins D2 and D3, with cutting-edge computational techniques, several intriguing results are unfolded. From the top-notch candidates, dexamethasone is likely to inhibit the viral main protease (Mpro), with vitamin D3 exhibiting multitarget [Mpro, papain-like protease (PLpro), and nucleocapsid protein (N-pro)] roles and ciclesonide's dynamic flipping disinterring a cryptic allosteric site in the PLpro enzyme. The results rationalize why these drugs improve the health of COVID-19 patients. Understanding an enzyme's secret binding site is essential to understanding how the enzyme works and how to inhibit its function. Ciclesonide's allosteric inhibition could not only jeopardize PLpro's catalytic role in polyprotein processing but also make it less vulnerable to the host body's defense machinery. Hotspot residues in the identified allosteric site could be considered for effective therapeutic designs against PLpro | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Papain |2 NLM | |
| 650 | 7 | |a EC 3.4.22.2 |2 NLM | |
| 650 | 7 | |a Peptide Hydrolases |2 NLM | |
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| 650 | 7 | |a Dexamethasone |2 NLM | |
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| 650 | 7 | |a Antiviral Agents |2 NLM | |
| 650 | 7 | |a Protease Inhibitors |2 NLM | |
| 700 | 1 | |a Sen Gupta, Parth Sarthi |e verfasserin |4 aut | |
| 700 | 1 | |a Karmakar, Shaswata |e verfasserin |4 aut | |
| 700 | 1 | |a Biswal, Satyaranjan |e verfasserin |4 aut | |
| 700 | 1 | |a Mahanandia, Nimai Charan |e verfasserin |4 aut | |
| 700 | 1 | |a Rana, Malay Kumar |e verfasserin |4 aut | |
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