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Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2.
J Mol Model. 2021 Jun 24; 27(7):206.JM

Abstract

The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor.

Authors+Show Affiliations

Department of Health and Biological Sciences, Abasyn University, Peshawar, 25000, Pakistan.Foundation University Medical College, Foundation University Islamabad, DHA-I, Islamabad, 44000, Pakistan. yasir.waheed@fui.edu.pk.Department of Biotechnology, Faculty of Life Sciences and Informatics, Balochistan University of Information Technology Engineering and Management Sciences, Quetta, Pakistan.NUMS Department of Biological Sciences, National University of Medical Sciences, Abid Majeed Rd, The Mall, Rawalpindi, Pakistan.NUMS Department of Biological Sciences, National University of Medical Sciences, Abid Majeed Rd, The Mall, Rawalpindi, Pakistan.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

34169390

Citation

Ahmad, Sajjad, et al. "Molecular Screening of Glycyrrhizin-based Inhibitors Against ACE2 Host Receptor of SARS-CoV-2." Journal of Molecular Modeling, vol. 27, no. 7, 2021, p. 206.
Ahmad S, Waheed Y, Abro A, et al. Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2. J Mol Model. 2021;27(7):206.
Ahmad, S., Waheed, Y., Abro, A., Abbasi, S. W., & Ismail, S. (2021). Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2. Journal of Molecular Modeling, 27(7), 206. https://doi.org/10.1007/s00894-021-04816-y
Ahmad S, et al. Molecular Screening of Glycyrrhizin-based Inhibitors Against ACE2 Host Receptor of SARS-CoV-2. J Mol Model. 2021 Jun 24;27(7):206. PubMed PMID: 34169390.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Molecular screening of glycyrrhizin-based inhibitors against ACE2 host receptor of SARS-CoV-2. AU - Ahmad,Sajjad, AU - Waheed,Yasir, AU - Abro,Asma, AU - Abbasi,Sumra Wajid, AU - Ismail,Saba, Y1 - 2021/06/24/ PY - 2021/01/06/received PY - 2021/06/02/accepted PY - 2021/6/25/entrez PY - 2021/6/26/pubmed PY - 2021/7/2/medline KW - ACE-2 KW - Glycyrrhizin KW - MMGB/PBSA KW - SARS-CoV-2 KW - Simulation KW - Virtual screening SP - 206 EP - 206 JF - Journal of molecular modeling JO - J Mol Model VL - 27 IS - 7 N2 - The interaction between SARS-CoV-2 Spike protein and angiotensin-converting enzyme 2 (ACE2) is essential to viral attachment and the subsequent fusion process. Interfering with this event represents an attractive avenue for the development of therapeutics and vaccine development. Here, a hybrid approach of ligand- and structure-based virtual screening techniques were employed to disclose similar analogues of a reported antiviral phytochemical, glycyrrhizin, targeting the blockade of ACE2 interaction with the SARS-CoV-2 Spike. A ligand-based similarity search using a stringent cut-off revealed 40 FDA-approved compounds in DrugBank. These filtered hits were screened against ACE2 using a blind docking approach to determine the natural binding tendency of the compounds with ACE2. Three compounds, deslanoside, digitoxin, and digoxin, were reported to show strong binding with ACE2. These compounds bind at the H1-H2 binding pocket, in a manner similar to that of glycyrrhizin which was used as a control. To achieve consistency in the docking results, docking calculations were performed via two sets of docking software that predicted binding energy as ACE2-Deslanoside (AutoDock, -10.3 kcal/mol and DockThor, -9.53 kcal/mol), ACE2-Digitoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.84 kcal/mol), and ACE2-Digoxin (AutoDock, -10.6 kcal/mol and DockThor, -8.81 kcal/mol). The docking results were validated by running molecular simulations in aqueous solution that demonstrated the stability of ACE2 with no major conformational changes in the ligand original binding mode (~ 2 Å average RMSD). Binding interactions remained quite stable with an increased potential for getting stronger as the simulation proceeded. MMGB/PBSA binding free energies were also estimated and these supported the high stability of the complexes compared to the control (~ -50 kcal/mol net MMGB/PBSA binding energy versus ~ -30 kcal/mol). Collectively, the data demonstrated that the compounds shortlisted in this study might be subjected to experimental evaluation to uncover their real blockade capacity of SARS-CoV-2 host ACE2 receptor. SN - 0948-5023 UR - https://www.unboundmedicine.com/medline/citation/34169390/Molecular_screening_of_glycyrrhizin_based_inhibitors_against_ACE2_host_receptor_of_SARS_CoV_2_ L2 - https://dx.doi.org/10.1007/s00894-021-04816-y DB - PRIME DP - Unbound Medicine ER -