期刊
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
卷 40, 期 6, 页码 2701-2714出版社
TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2020.1841681
关键词
SARS-CoV-2; protein-protein interactions (PPIs); spike glycoprotein; virtual screening; molecular docking; molecular dynamics
SARS-CoV-2 is a pandemic that has caused global health concerns, with no effective drugs available for treatment. Research has shown that protein-protein interactions between the virus and host cells play a crucial role in the pathogenesis. In this study, a network medicine approach was used to virtually screen 55 compounds and identify potential molecules that can block the entry of the virus by binding to its spike glycoprotein.
SARS-CoV-2 has become a pandemic causing a serious global health concern. The absence of effective drugs for treatment of the disease has caused its rapid spread on a global scale. Similarly to the SARS-CoV, the SARS-CoV-2 is also involved in a complex interplay with the host cells. This infection is characterized by a diffused alveolar damage consistent with the Acute Respiratory Disease Syndrome (ARDS). To explore the complex mechanisms of the disease at the system level, we used a network medicine tools approach. The protein-protein interactions (PPIs) between the SARS-CoV and the associated human cell proteins are crucial for the viral pathogenesis. Since the cellular entry of SARS-CoV-2 is accomplished by binding of the spike glycoprotein binding domain (RBD) to the human angiotensin-converting enzyme 2 (hACE2), a molecule that can bind to the spike RDB-hACE2 interface could block the virus entry. Here, we performed a virtual screening of 55 compounds to identify potential molecules that can bind to the spike glycoprotein and spike-ACE2 complex interface. It was found that the compound ethyl 1-{3-[(2,4-dichlorobenzyl) carbamoyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolinyl}-4-piperidine carboxylate (the S54 ligand) and ethyl 1-{3-[(2,4-dichlorobenzyl) carbamoyl]-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinolinyl}-4 piperazine carboxylate (the S55 ligand) forms hydrophobic interactions with Tyr41A, Tyr505B and Tyr553B, Leu29A, Phe495B, respectively of the spike glycoprotein, the hotspot residues in the spike glycoprotein RBD-hACE2 binding interface. Furthermore, molecular dynamics simulations and free energy calculations using the MM-GBSA method showed that the S54 ligand is a stronger binder than a known SARS-CoV spike inhibitor SSAA09E3 (N-(9,10-dioxo-9, 10-dihydroanthracen-2-yl) benzamide). Communicated by Ramaswamy H. Sarma
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