Abstract
COVID-19 pandemic caused by SARS-CoV-2 virus has become a global health emergency. Although new vaccines have been generated and being implicated, discovery and application of novel preventive and control measures are warranted. We aimed to identify compound/s that may possess the potential to either block the entry of virus to host cells or attenuate its replication upon infection. Using host cell surface receptor expression (Angiotensin-converting enzyme 2 (ACE2) and Transmembrane protease serine 2 (TMPRSS2) analysis as an assay, we earlier screened several synthetic and natural compounds and identified candidates that showed ability to downregulate their expression. Here, we report experimental and computational analyses of two small molecules, Mortaparib and MortaparibPlus that were initially identified as dual novel inhibitors of mortalin and PARP-1, for their activity against SARS-CoV-2. In silico analyses showed that MortaparibPlus, but not Mortaparib, stably binds into the catalytic pocket of TMPRSS2. In vitro analysis of control and treated cells revealed that MortaparibPlus caused downregulation of ACE2 and TMPRSS2; Mortaparib did not show any effect. Furthermore, computational analysis on SARS-CoV-2 main protease (Mpro) that also predicted the inhibitory activity of MortaparibPlus. However, cell based anti-virus drug screening assay showed 30~60% viral inhibition in cells treated with non-toxic doses of either MortaparibPlus or Mortaparib. The data suggests that these two closely related compounds possess multimodal anti-COVID 19 activities. Whereas MortaparibPlus works through direct interactions/effects on the host cell surface receptors (ACE2 and TMPRSS2) and the virus protein (Mpro), Mortaparib involves independent mechanisms, elucidation of which warrants further studies.
Highlights
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus that belongs to Coronaviradae family
We used glide flexible molecular docking and examined if Mortaparib or MortaparibPlus could interact with TMPRSS2 and ACE2 and act as their inhibitors
In the best binding pose, it showed hydrogen bonding with Gln76 of ACE2 and Ser441 and Ser436 of TMPRSS2 (Figs. 1B and 1C). When these docked complexes were subjected to Molecular Dynamics (MD) simulations to check the binding stability and consistency of the crucial interactions, Mortaparib could not interact stably with any of these two targets
Summary
The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus that belongs to Coronaviradae family. Coronaviruses are divided into four major genera ( and ). Among these, the former two are known to infect mammals while the latter two infect birds. SARS-CoV-2 is a -coronavirus [10,11,12]. The outbreak of novel coronavirus disease 2019 (COVID-19) in the Wuhan province of China by the SARS-CoV-2 was declared a global pandemic by the World Health Organization [13]. As of September 10, 2021, there are >223 million cases reported with >4.6 million deaths worldwide as recorded by WHO
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