Systemic <i>In Silico</i> Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

Xu, Chi; Ke, Zunhui; Liu, Chuandong; Wang, Zhihao; Liu, Denghui; Zhang, Lei; Wang, Jingning; He, Wenjun; Xu, Zhimeng; Li, Yanqing; Yang, Yanan; Huang, Zhaowei; Lv, Panjing; Wang, Xin; Han, Dali; Li, Yan; Qiao, Nan; Liu, Bing

doi:10.1021/acs.jcim.0c00821

Cited by 38 publications

(39 citation statements)

References 85 publications

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“…In this extreme situation (OSIS), the unique treatment possible suggested by our model is an inhibitor of Nsp5 like Saquinavir (Xun et al, 2020). In this case, the OSIS is completely shut down, which indirectly implies the down production of ACE2.…”

Section: Discussionmentioning

confidence: 88%

“…In this case, the OSIS is completely shut down, which indirectly implies the down production of ACE2. Saquinavir is an anti-retroviral drug used against the main protease of HIV-1 (Bensussen et al, 2018;Xun et al, 2020), with some undesirable effects like diarrhea, abdominal pain, and nausea. We suggest that this drug could be a plausible treatment against the effects of SARS-CoV-2 in acute lung inflammation, and as a complement to the new vaccine against this coronavirus.…”

Section: Discussionmentioning

confidence: 99%

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SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Dynamical Mathematical Model

Díaz¹,

Álvarez-Buylla²,

Bensussen³

2021

Preprint

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In the present work we propose a dynamical mathematical model of the lung cells inflammation process in response to SARS-CoV-2 infection. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. In presence of the virus the translation rates of NF kB and IkB arise to a high constant value, and when the translation rate of IL-6 also increases above the threshold value of 7 pg mL-1 s-1 the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. Our model shows how such over stimulated immune state becomes autonomous of the signals from other immune cells such as macrophages and lymphocytes, and does not shut down by itself. We also show that in the context of the dynamical model presented here, Dexamethasone or Nimesulide have little effect on such inflammation state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5.To that end, our model suggest that drugs like Saquinavir may be useful. In this form, our model suggests that Nsp5 is effectively a central node underlying the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. Nsp5 seems to be the switch to start inflammation, the consequent overproduction of the ACE2 receptor, and an important underlying cause of the most severe cases of COVID19.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Dynamical Mathematical Model

Díaz¹,

Álvarez-Buylla²,

Bensussen³

2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Given this, there has been an immense focus on identifying compounds for testing against the coronavirus' main protease [38,39]. In silico drug-discovery tools have been widely used to expedite this process [40,41]. Here, we designed and implemented a unique fragment-guided pharmacophore-based in silico approach.…”

Section: Discussionmentioning

confidence: 99%

Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

et al. 2020

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The ongoing pandemic caused by the novel coronavirus has been the greatest global health crisis since the Spanish flu pandemic of 1918. Thus far, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in over 1 million deaths, and there is no cure or vaccine to date. The recently solved crystal structure of the SARS-CoV-2 main protease has been a major focus for drug-discovery efforts. Here, we present a fragment-guided approach using ZINCPharmer, where 17 active fragments known to bind to the catalytic centre of the SARS-CoV-2 main protease (SARS-CoV-2 Mpro) were used as pharmacophore queries to search the ZINC databases of natural compounds and natural derivatives. This search yielded 134 hits that were then subjected to multiple rounds of in silico analyses, including blind and focused docking against the 3D structure of the main protease. We scrutinised the poses, scores, and protein–ligand interactions of 15 hits and selected 7. The scaffolds of the seven hits were structurally distinct from known inhibitor scaffolds, thus indicating scaffold novelty. Our work presents several novel scaffolds as potential candidates for experimental validation against SARS-CoV-2 Mpro.

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“…In this case, the OSIS is completely shut down, which indirectly implies the down production of ACE2. Saquinavir is an anti-retroviral drug used against the main protease of HIV-1 (Bensussen et al, 2018;Xun et al, 2020), with some undesirable effects like diarrhea, abdominal pain, and nausea. This could be a plausible treatment against the effects of SARS-CoV-2 in acute lung inflammation, and as a complement to the new vaccine against this coronavirus.…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Mathematical Model

Díaz¹,

Álvarez-Buylla²,

Bensussen³

2020

Preprint

View full text Add to dashboard Cite

In the present work we propose a mathematical model of the process of inflammation in lung cells in response to SARS-CoV-2 infection from which a plausible scenario for the dynamics of this process arise. In this scenario the main protease Nsp5 enhances the inflammatory process, increasing the levels of NF kappaB, IL-6, Cox2, and PGE2 with respect to a reference state without the virus. When in presence of the virus the translation rates of NF kappaB and IkB are increased to a high constant value, and the translation rate of IL-6 is increased above the threshold value of 7 nM s-1, the model predicts a persistent over stimulated immune state with high levels of the cytokine IL-6. This over stimulated immune state becomes autonomous of the signals from other immune cells like macrophages and lymphocytes, and does not shut down by itself. Dexamethasone or Nimesulide have little effect on this state of the infected lung cell, and the only form to suppress it is with the inhibition of the activity of the viral protein Nsp5 with drugs like Saquinavir. In this form, our model suggests that Nsp5 is effectively the cause of the severe acute lung inflammation during SARS-CoV-2 infection. The persistent production of IL-6 by lung cells can be one of the causes of the cytokine storm observed in critical patients with COVID19. From an evolutive point of view, the use of Nsp5 as the switch to start inflammation, and the consequent overproduction of the ACE2 receptor, is the probable reason of the increased dangerousness of SARS-CoV-2 with respect to SARS-CoV.

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Systemic In Silico Screening in Drug Discovery for Coronavirus Disease (COVID-19) with an Online Interactive Web Server

Cited by 38 publications

References 85 publications

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Dynamical Mathematical Model

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Dynamical Mathematical Model

Novel Small-Molecule Scaffolds as Candidates against the SARS Coronavirus 2 Main Protease: A Fragment-Guided in Silico Approach

SARS-CoV-2 Nsp5 Protein Causes Acute Lung Inflammation: A Mathematical Model

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