Natural phytochemicals, Phenformin, and Docosahexaenoic acid (DHA) as a Novel Inhibitors of IL-6 and ACE2 receptors, a Therapeutic Strategy for targeting COVID-19 Cell Entry and Cytokine Storm. An insilico Approach
Authors: Ahmed Amr kamel khalil , Elkazzaz Mahmoud 
Published: September 2021

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 regulatory, 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, interleukin-6 could play a key role. The significant role of IL-6 in COVID-19 pathogenesis was established in a wide variety of researches, which reported that the plasma concentration of IL-6 was raised in COVID-19 patients with severe symptoms. COVID-19 spike protein 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 or inhibit IL-6 activity may possibly help COVID-19 patients avoid a cytokine storm and save their lives through inhibiting IL-6 and preventing SARS-CoV-2 RBD attachment to ACE2. Herein we made a docking based screening for some natural phytochemicals and drugs that could be repurposed according to our findings to counter COVID-19 cell entry and inhibit the hyper activation of IL-6. Our results revealed that a five phytochemicals including Epigallocatechin gallate (EGCG), bromelain, luteolin, vitexin and isovitexin) showed a high binding affinities with best interactions with the active sites of IL-6. The binding affinities of these phytochemicals including, EGCG, bromelain, luteolin, vitexin and isovitexin with IL-6 were (-7.7, -6.7, -7.4, -7.2 and − 7.3 ), respectively. In addition to, phenformin showed a high binding affinity with best interactions with the active sites of IL-6 and ACE2. The binding affinity of phenformin with IL-6 was (-7.4) and with ACE 2 ( -7.2). Docosahexaenoic acid (DHA) had a moderate binding affinity and moderate interactions with the active sites of IL-6 and had a high binding affinity with best interactions with ACE2 active sites. The binding affinity of Docosahexaenoic acid(DHA) with IL-6 was (-5.3) and with AC2 (-6.3).ConclusionProposing possible IL-6 inhibitors with less adverse effects has been suggested as a way to aid COVID-19 patients who are suffering from severe cytokine storms. This study has been designed to elucidate the potential of potent antiviral phytocompounds as well as phenformin and Docosahexaenoic acid (DHA) as a potent ACE2 and IL-6 inhibitors. The compounds interact with different active sites of IL6 and ACE2 which are involved in direct or indirect contacts with the ACE2 and IL-6 receptors which might act as potential blockers of functional ACE2 and IL-6 receptor complex. It worth mentioning that phenformin which showed high binding affinity with both ACE2 and IL-6 is currently under investigation for treating COVID-19 ClinicalTrials.gov Identifier: NCT05003492