Phenothiazines as dual inhibitors of SARS-CoV-2 main protease and COVID-19 inflammation.

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From: Canadian Journal of Chemistry(Vol. 99, Issue 10)
Publisher: NRC Research Press
Document Type: Report
Length: 6,158 words
Lexile Measure: 1990L

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Abstract :

COVID-19, caused by the severe acute respiratory coronavirus 2 (SARS-CoV-2), currently has no treatment for acute infection. The main protease ([M.sup.pro]) of SARS-CoV-2 is an essential enzyme for viral replication and an attractive target for disease intervention. The phenothiazine moiety has demonstrated drug versatility for biological systems, including inhibition of butyrylcholinesterase, a property important in the cholinesterase anti-inflammatory cascade. Nineteen phenothiazine drugs were investigated using in silico modelling techniques to predict binding energies and inhibition constants ([K.sub.i] values) with SARS-CoV-2 [M.sup.pro]. Because most side-effects of phenothiazines are due to interactions with various neurotransmitter receptors and transporters, phenothiazines with few such interactions were also investigated. All compounds were found to bind to the active site of SARS-CoV-2 [M.sup.pro] and showed [K.sub.i] values ranging from 1.30 to 52.4 [micro]M in a rigid active site. Nine phenothiazines showed inhibition constants Key words: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), COVID-19, main protease ([M.sup.pro]), phenothiazine, in silico molecular modelling, Molecular Operating Environment (MOE). Il n'existe actuellement aucun traitement de la forme aigue de la COVID-19, la maladie causee par l'infection par le coronavirus du syndrome respiratoire aigu severe 2 (SRAS-CoV-2). La principale protease ([M.sup.pro]) du SRAS-CoV-2 est une enzyme essentielle pour la replication virale et une cible interessante pour l'intervention contre la maladie. Le motif phenothiazine s'est revele posseder des proprietes medicamenteuses polyvalentes dans des systemes biologiques, y compris linhibition de la butyrylcholinesterase, une propriete importante dans la cascade anti-inflammatoire de la cholinesterase. Nous avons etudie 19 medicaments derives de la phenothiazine a l'aide de techniques de modelisation in silico pour predire leur energie de liaison et leur constante d'inhibition ([K.sub.i]) a l'egard de la [M.sup.pro] du SRAS-CoV-2. Etant donne que la plupart des effets secondaires des phenothiazines sont dus a des interactions avec divers recepteurs et transporteurs de neurotransmetteurs, nous avons egalement etudie des phenothiazines ayant peu d'interactions de ce type. Tous les composes se sont lies au site actif de la [M.sup.pro] du SRAS-COV-2 et ont montre des valeurs de [K.sub.i] variant de 1,30 a 52,4 [micro]M. Neuf phenothiazines ont montre des constantes d'inhibition Mots-cles : coronavirus du syndrome respiratoire aigu severe 2 (SRAS-CoV-2), COVID-19, protease principale ([M.sup.pro]), phenothiazine, modelisation moleculaire in silico, plateforme logicielle Molecular Operating Environment (MOE).

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Gale Document Number: GALE|A678582823