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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.
J Proteome Res. 2020 11 06; 19(11):4706-4717.JP

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.

Authors+Show Affiliations

PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.PG and Research Department of Chemistry, Sree Narayana College, Kollam, Kerala 691001, India.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32960061

Citation

Achutha, A S., et al. "Theoretical Insights Into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and in Silico Screening of Main Protease Inhibitors." Journal of Proteome Research, vol. 19, no. 11, 2020, pp. 4706-4717.
Achutha AS, Pushpa VL, Suchitra S. Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors. J Proteome Res. 2020;19(11):4706-4717.
Achutha, A. S., Pushpa, V. L., & Suchitra, S. (2020). Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors. Journal of Proteome Research, 19(11), 4706-4717. https://doi.org/10.1021/acs.jproteome.0c00683
Achutha AS, Pushpa VL, Suchitra S. Theoretical Insights Into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and in Silico Screening of Main Protease Inhibitors. J Proteome Res. 2020 11 6;19(11):4706-4717. PubMed PMID: 32960061.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Theoretical Insights into the Anti-SARS-CoV-2 Activity of Chloroquine and Its Analogs and In Silico Screening of Main Protease Inhibitors. AU - Achutha,A S, AU - Pushpa,V L, AU - Suchitra,Surendran, Y1 - 2020/10/07/ PY - 2020/9/23/pubmed PY - 2020/12/1/medline PY - 2020/9/22/entrez KW - 3CLpro KW - COVID-19 KW - SARS-CoV-2 KW - antiviral screening KW - chloroquine KW - hydroxychloroquine KW - molecular docking KW - molecular dynamics KW - regression SP - 4706 EP - 4717 JF - Journal of proteome research JO - J Proteome Res VL - 19 IS - 11 N2 - 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. SN - 1535-3907 UR - https://www.unboundmedicine.com/medline/citation/32960061/Theoretical_Insights_into_the_Anti_SARS_CoV_2_Activity_of_Chloroquine_and_Its_Analogs_and_In_Silico_Screening_of_Main_Protease_Inhibitors_ L2 - https://doi.org/10.1021/acs.jproteome.0c00683 DB - PRIME DP - Unbound Medicine ER -