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Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors.
Achutha, A S; Pushpa, V L; Suchitra, Surendran.
  • Achutha AS; PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.
  • Pushpa VL; PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.
  • Suchitra S; PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.
J Proteome Res ; 19(11): 4706-4717, 2020 11 06.
Article in English | MEDLINE | ID: covidwho-950742
ABSTRACT
Corona virus disease (COVID-19) is a dangerous disease rapidly spreading all over the world today. Currently there are no treatment options for it. Drug repurposing studies explored the potency of antimalarial drugs, chloroquine and hydroxychloroquine, against SARS-CoV-2 virus. These drugs can inhibit the viral protease, called chymotrypsin-like cysteine protease, also known as Main protease (3CLpro); hence, we studied the binding efficiencies of 4-aminoquinoline and 8-aminoquinoline analogs of chloroquine. Six compounds furnished better binding energies than chloroquine and hydroxychloroquine. The interactions with the active site residues especially with Cys145 and His41, which are involved in catalytic diad for proteolysis, make these compounds potent main protease inhibitors. A regression model correlating binding energy and the molecular descriptors for chloroquine analogs was generated with R2 = 0.9039 and Q2 = 0.8848. This model was used to screen new analogs of primaquine and molecules from the Asinex compound library. The docking and regression analysis showed these analogs to be more potent inhibitors of 3CLpro than hydroxychloroquine and primaquine. The molecular dynamic simulations of the hits were carried out to determine the binding stabilities. Finally, we propose four compounds that show drug likeness toward SARS-CoV-2 that can be further validated through in vitro and in vivo studies.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Protease Inhibitors / Cysteine Endopeptidases / Chloroquine / Viral Nonstructural Proteins / Coronavirus Infections / Betacoronavirus Type of study: Prognostic study Limits: Humans Language: English Journal: J Proteome Res Journal subject: Biochemistry Year: 2020 Document Type: Article Affiliation country: Acs.jproteome.0c00683

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Pneumonia, Viral / Protease Inhibitors / Cysteine Endopeptidases / Chloroquine / Viral Nonstructural Proteins / Coronavirus Infections / Betacoronavirus Type of study: Prognostic study Limits: Humans Language: English Journal: J Proteome Res Journal subject: Biochemistry Year: 2020 Document Type: Article Affiliation country: Acs.jproteome.0c00683