Scholarlink

<p>Since 2019, SARS-CoV-2 has undergone rapid evolution and acquired resistance to various therapeutics. Its high mutation rate threatens the long-term efficacy of vaccines. The development of host-directed antivirals presents a promising strategy for combat SARS-CoV-2 emerging variants of concern. The entry of SARS-CoV-2 into target cells necessitates the activation of its surface spike protein (S) by host proteases. This process involves the serine protease TMPRSS2 and the cysteine proteases Cathepsins L and B, which together enable two distinct pathways for the virus to infiltrate cells. Guanidine derivatives are highly significant in inhibiting protease activity by effectively mimicking their substrates. In this study, we investigated a set of 25 bromopyrrole marine alkaloids, collectively known as Nagelamides, using advanced combinatorial computational methods, including molecular docking, normal mode (NMA) analysis and molecular dynamics simulations (MD). Docking analysis demonstrated that among the tested compounds, Nagelamide H displayed the lowest binding free energies of -9.52, -9.59, and -10.53 kcal/mol against TMPRSS2, Cathepsins L and B, respectively. The docking complexes underwent normal mode analysis using the IMOD server and a 500 ns molecular dynamics simulation. The results demonstrated enhanced stability of TMPRSS2, Cathepsin L, and Cathepsin B when complexed with Nagelamide H. These findings highlight Nagelamide H as a potential dual-pathway inhibitor and suggest its broader application in antiviral strategies targeting host protease-mediated viral entry. Experimental validation, <i>in vitro</i> enzymatic and cell-based assays followed by <i>in vivo</i> studies will be required to confirm its antiviral efficacy and safety.</p> Graphical abstract

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Bromopyrrole guanidine marine alkaloids as inhibitors of SARS-CoV-2 entry pathways: insights from molecular docking, normal mode analysis, and molecular dynamics simulations

  • 期刊论文

  • 发表日期：

    2026年7月13日

查看全文
  • Wafa Tachoua,
  • Mohamed Kabrine,
  • Ali Nizakat,
  • Zaheer Ul-Haq

摘要

Since 2019, SARS-CoV-2 has undergone rapid evolution and acquired resistance to various therapeutics. Its high mutation rate threatens the long-term efficacy of vaccines. The development of host-directed antivirals presents a promising strategy for combat SARS-CoV-2 emerging variants of concern. The entry of SARS-CoV-2 into target cells necessitates the activation of its surface spike protein (S) by host proteases. This process involves the serine protease TMPRSS2 and the cysteine proteases Cathepsins L and B, which together enable two distinct pathways for the virus to infiltrate cells. Guanidine derivatives are highly significant in inhibiting protease activity by effectively mimicking their substrates. In this study, we investigated a set of 25 bromopyrrole marine alkaloids, collectively known as Nagelamides, using advanced combinatorial computational methods, including molecular docking, normal mode (NMA) analysis and molecular dynamics simulations (MD). Docking analysis demonstrated that among the tested compounds, Nagelamide H displayed the lowest binding free energies of -9.52, -9.59, and -10.53 kcal/mol against TMPRSS2, Cathepsins L and B, respectively. The docking complexes underwent normal mode analysis using the IMOD server and a 500 ns molecular dynamics simulation. The results demonstrated enhanced stability of TMPRSS2, Cathepsin L, and Cathepsin B when complexed with Nagelamide H. These findings highlight Nagelamide H as a potential dual-pathway inhibitor and suggest its broader application in antiviral strategies targeting host protease-mediated viral entry. Experimental validation, in vitro enzymatic and cell-based assays followed by in vivo studies will be required to confirm its antiviral efficacy and safety.

Graphical abstract