Natural phytochemicals, phenformin, and docosahexaenoic acid (DHA) as Novel Inhibitors of leukotriene B4 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. (An In-silico Approach)

Abstract

Cytokine storm syndrome (CSS) is a life-threatening consequence of inflammatory, immunological illnesses; it can also occur with COVID-19 infection. CSS is characterized by a disruption in cytokine synthesis, including regula-tory, pro-inflammatory, and anti-inflammatory cytokines, resulting in pathologic stimulation of innate in addition to adaptive (Th17 and Th1 mediated) response. In the pathophysiology of CSS, leukotriene could play a key role. The sig-nificant role of leukotriene in COVID-19 pathogenesis was established in a wide variety of research, which reported that the plasma concentration of leukotriene was raised in COVID-19 patients with severe symptoms. COVID-19 spike pro-tein binding to angiotensin-converting enzyme 2 (ACE2), the virus’s cellular receptor, causes a cascade of molecular processes that could result in hyperinflammation, which may lead to cytokine storm. Therefore, the development of new natural therapies and repurposing some drugs such as Phenformin and docosahexaenoic acid that could compete with COVID-19 for ACE2 binding activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives by preventing SARS-CoV-2 RBD attachment to ACE2. Herein, we made docking-based screening for some natural phytochemicals and drugs that could be repur-posed according to our findings to counter COVID-19 cell entry and inhibit the hyperactivation of leukotriene B4. Our results revealed that phytochemicals including (bromelain, epigallocatechin gallate, isovitexin, luteolin, metformin, quercetin, and vitexin) showed high binding affinities with best interactions with the active sites of leukotri-ene B4. The binding affinities of these phytochemicals were (-7.2, -8.3, -7.2, -5.0, -4.11, -5.1 and -7.7kcal/mol), respectively. In addition, Phenformin and Docosahexaenoic acid (DHA) showed a high binding affinity with the best interactions with the active sites of ACE2. The binding affinity of Phenformin and docosahexaenoic acid (DHA) with ACE 2 was (-7.2) and (-6.3), respectively. As a result, these compounds could be used as a new therapy to prevent COVID-19 cell entrance and associ-ated inflammatory consequences.