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Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases.
J Nanosci Nanotechnol. 2021 04 01; 21(4):2075-2089.JN

Abstract

In the current pandemic situation raised due to COVID-19, drug reuse is emerging as the first line of treatment. The viral agent that causes this highly contagious disease and the acute respiratory syndrome coronavirus (SARS-CoV) share high nucleotide similarity. Therefore, it is structurally expected that many existing viral targets are similar to the first SARS-CoV, probably being inhibited by the same compounds. Here, we selected two viral proteins based on their vital role in the viral life cycle: Structure of the main protease SARS-CoV-2 and the structural base of the SARS-CoV-2 protease 3CL, both supporting the entry of the virus into the human host. The approved drugs used were azithromycin, ritonavir, lopinavir, oseltamivir, ivermectin and heparin, which are emerging as promising agents in the fight against COVID-19. Our hypothesis behind molecular coupling studies is to determine the binding affinities of these drugs and to identify the main amino acid residues that play a fundamental role in their mechanism of action. Additional studies on a wide range of FDA-approved drugs, including a few more protein targets, molecular dynamics studies, in vitro and biological in vivo evaluation are needed to identify combination therapy targeted at various stages of the viral life cycle. In our experiment in silico, based mainly on the molecular coupling approach, we investigated six different types of pharmacologically active drugs, aiming at their potential application alone or in combination with the reuse of drugs. The ligands showed stable conformations when analyzing the affinity energy in both proteases: ivermectin forming a stable complex with the two proteases with values -8.727 kcal/mol for Main Protease and -9.784 kcal/mol for protease 3CL, Heparin with values of -7.647 kcal/mol for the Main protease and -7.737 kcal/mol for the 3CL protease. Both conform to the catalytic site of the proteases. Our studies can provide an insight into the possible interactions between ligands and receptors, through better conformation. The ligands ivermectin, heparin and ritonavir showed stable conformations. Our in-silica docking data shows that the drugs we have identified can bind to the binding compartment of both proteases, this strongly supports our hypothesis that the development of a single antiviral agent targeting Main protease, or 3CL protease, or an agent used in combination with other potential therapies, it could provide an effective line of defense against diseases associated with coronaviruses.

Authors+Show Affiliations

Laboratory of Preparation and Computation of Nanomaterials (LPCN), Federal University of Pará, C. P. 479, 66075-110 Belem, PA, Brazil.Laboratory of Preparation and Computation of Nanomaterials (LPCN), Federal University of Pará, C. P. 479, 66075-110 Belem, PA, Brazil.Federal University of Lavras (UFLA), Chemistry Department, 37200-000 - Lavras, MG, Brazil.Post-Graduation Program in Engineering of Natural Resources of the Amazon, Institute of Technology (ITEC), Federal University of Pará, C. P. 2626, 66.050-540, Belem, PA, Brazil.Universidade Federal de Jataí. Rodovia BR-364, 75.8016-15 - Jataí, GO - Brazil.Federal University of the South and Southeast of Pará. FL 17, QD 04, LT Especial, New Marabá, 68.505-080 - Marabá, PA - Brazil.Laboratory of Preparation and Computation of Nanomaterials (LPCN), Federal University of Pará, C. P. 479, 66075-110 Belem, PA, Brazil.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33500022

Citation

Arouche, Tiago da Silva, et al. "Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting With Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases." Journal of Nanoscience and Nanotechnology, vol. 21, no. 4, 2021, pp. 2075-2089.
Arouche TDS, Martins AY, Ramalho TC, et al. Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases. J Nanosci Nanotechnol. 2021;21(4):2075-2089.
Arouche, T. D. S., Martins, A. Y., Ramalho, T. C., Júnior, R. N. C., Costa, F. L. P., Filho, T. S. A., & Neto, A. M. J. C. (2021). Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases. Journal of Nanoscience and Nanotechnology, 21(4), 2075-2089. https://doi.org/10.1166/jnn.2021.19029
Arouche TDS, et al. Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting With Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases. J Nanosci Nanotechnol. 2021 04 1;21(4):2075-2089. PubMed PMID: 33500022.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular Docking of Azithromycin, Ritonavir, Lopinavir, Oseltamivir, Ivermectin and Heparin Interacting with Coronavirus Disease 2019 Main and Severe Acute Respiratory Syndrome Coronavirus-2 3C-Like Proteases. AU - Arouche,Tiago da Silva, AU - Martins,Anderson Yuri, AU - Ramalho,Teodorico de Castro, AU - Júnior,Raul Nunes Carvalho, AU - Costa,Fabio Luiz Paranhos, AU - Filho,Tarciso Silva de Andrade, AU - Neto,Antonio Maia Jesus Chaves, PY - 2021/1/27/entrez PY - 2021/1/28/pubmed PY - 2021/2/9/medline SP - 2075 EP - 2089 JF - Journal of nanoscience and nanotechnology JO - J Nanosci Nanotechnol VL - 21 IS - 4 N2 - In the current pandemic situation raised due to COVID-19, drug reuse is emerging as the first line of treatment. The viral agent that causes this highly contagious disease and the acute respiratory syndrome coronavirus (SARS-CoV) share high nucleotide similarity. Therefore, it is structurally expected that many existing viral targets are similar to the first SARS-CoV, probably being inhibited by the same compounds. Here, we selected two viral proteins based on their vital role in the viral life cycle: Structure of the main protease SARS-CoV-2 and the structural base of the SARS-CoV-2 protease 3CL, both supporting the entry of the virus into the human host. The approved drugs used were azithromycin, ritonavir, lopinavir, oseltamivir, ivermectin and heparin, which are emerging as promising agents in the fight against COVID-19. Our hypothesis behind molecular coupling studies is to determine the binding affinities of these drugs and to identify the main amino acid residues that play a fundamental role in their mechanism of action. Additional studies on a wide range of FDA-approved drugs, including a few more protein targets, molecular dynamics studies, in vitro and biological in vivo evaluation are needed to identify combination therapy targeted at various stages of the viral life cycle. In our experiment in silico, based mainly on the molecular coupling approach, we investigated six different types of pharmacologically active drugs, aiming at their potential application alone or in combination with the reuse of drugs. The ligands showed stable conformations when analyzing the affinity energy in both proteases: ivermectin forming a stable complex with the two proteases with values -8.727 kcal/mol for Main Protease and -9.784 kcal/mol for protease 3CL, Heparin with values of -7.647 kcal/mol for the Main protease and -7.737 kcal/mol for the 3CL protease. Both conform to the catalytic site of the proteases. Our studies can provide an insight into the possible interactions between ligands and receptors, through better conformation. The ligands ivermectin, heparin and ritonavir showed stable conformations. Our in-silica docking data shows that the drugs we have identified can bind to the binding compartment of both proteases, this strongly supports our hypothesis that the development of a single antiviral agent targeting Main protease, or 3CL protease, or an agent used in combination with other potential therapies, it could provide an effective line of defense against diseases associated with coronaviruses. SN - 1533-4899 UR - https://www.unboundmedicine.com/medline/citation/33500022/Molecular_Docking_of_Azithromycin,_Ritonavir,_Lopinavir,_Oseltamivir,_Ivermectin_and_Heparin_Interacting_with_Coronavirus_Disease_2019_Main_and_Severe_Acute_Respiratory_Syndrome_Coronavirus-2_3C-Like_Proteases. L2 - https://www.ingentaconnect.com/openurl?genre=article&issn=1533-4899&volume=21&issue=4&spage=2075&aulast=Arouche DB - PRIME DP - Unbound Medicine ER -