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Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors.
Virus Res. 2020 09; 286:198068.VR

Abstract

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested.

Authors+Show Affiliations

Department of Biology, Structural Bioinformatics Group, University of Rome Tor Vergata, Rome, Italy.Department of Biology, Structural Bioinformatics Group, University of Rome Tor Vergata, Rome, Italy.Department of Biology, Structural Bioinformatics Group, University of Rome Tor Vergata, Rome, Italy. Electronic address: falconi@uniroma2.it.

Pub Type(s)

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

Language

eng

PubMed ID

32565126

Citation

Romeo, Alice, et al. "Targeting the SARS-CoV-2 Spike Glycoprotein Prefusion Conformation: Virtual Screening and Molecular Dynamics Simulations Applied to the Identification of Potential Fusion Inhibitors." Virus Research, vol. 286, 2020, p. 198068.
Romeo A, Iacovelli F, Falconi M. Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors. Virus Res. 2020;286:198068.
Romeo, A., Iacovelli, F., & Falconi, M. (2020). Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors. Virus Research, 286, 198068. https://doi.org/10.1016/j.virusres.2020.198068
Romeo A, Iacovelli F, Falconi M. Targeting the SARS-CoV-2 Spike Glycoprotein Prefusion Conformation: Virtual Screening and Molecular Dynamics Simulations Applied to the Identification of Potential Fusion Inhibitors. Virus Res. 2020;286:198068. PubMed PMID: 32565126.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Targeting the SARS-CoV-2 spike glycoprotein prefusion conformation: virtual screening and molecular dynamics simulations applied to the identification of potential fusion inhibitors. AU - Romeo,Alice, AU - Iacovelli,Federico, AU - Falconi,Mattia, Y1 - 2020/06/18/ PY - 2020/04/10/received PY - 2020/06/03/revised PY - 2020/06/16/accepted PY - 2020/6/23/pubmed PY - 2020/9/9/medline PY - 2020/6/23/entrez KW - Fusion inhibitors KW - Molecular dynamics KW - SARS-CoV-2 KW - Sequence alignment KW - Spike glycoprotein KW - Virtual screening SP - 198068 EP - 198068 JF - Virus research JO - Virus Res VL - 286 N2 - The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to a renewed interest in studying the role of the spike S glycoprotein in regulating coronavirus infections in the natural host. Taking advantage of the cryo-electron microscopy structure of SARS-CoV-2 S trimer in the prefusion conformation, we performed a virtual screening simulation with the aim to identify novel molecules that could be used as fusion inhibitors. The spike glycoprotein structure has been completed using modeling techniques and its inner cavity, needful for the postfusion transition of the trimer, has been scanned for the identification of strongly interacting available drugs. Finally, the stability of the protein-drug top complexes has been tested using classical molecular dynamics simulations. The free energy of interaction of the molecules to the spike protein has been evaluated through the MM/GBSA method and per-residue decomposition analysis. Results have been critically discussed considering previous scientific knowledge concerning the selected compounds and sequence alignments have been carried out to evaluate the spike glycoprotein similarity among the betacoronavirus family members. Finally, a cocktail of drugs that may be used as SARS-CoV-2 fusion inhibitors has been suggested. SN - 1872-7492 UR - https://www.unboundmedicine.com/medline/citation/32565126/Targeting_the_SARS_CoV_2_spike_glycoprotein_prefusion_conformation:_virtual_screening_and_molecular_dynamics_simulations_applied_to_the_identification_of_potential_fusion_inhibitors_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0168-1702(20)30383-X DB - PRIME DP - Unbound Medicine ER -