The in silico mechanism of hVKOR interaction with acetaminophen and its metabolite, as well as N-acetyl cysteine: caution on application in COVID-19 patients.

Acetaminophen and N-acetyl cysteine (NAC) are being used as supportive care in patients suffering from coronavirus disease 2019 (COVID-19). The coagulopathy and cerebral hemorrhage have been recently reported in these patients. Prolonged acetaminophen use increases the international normalized ratio (INR) and the risk of bleeding among patients taking anti-coagulants. Inhibition of vitamin K epoxide reductase (VKOR) by acetaminophen and NAC in chronic applications has been reported, however, detailed knowledge of the molecular mechanism and binding sites are not clear. Herein, we built the homology model of human VKOR (hVKOR) using ITASSER server, confirmed, and applied it for docking analysis of its interaction with acetaminophen and its metabolite, N-acetyl-p-benzoquinone imine (NAPQI), and NAC. We also calculated the lipophilicity and predicted the blood-brain-barrier (BBB) permeation of NAPQI by Swiss ADME. Our analysis showed that NAPQI and NAC, but not acetaminophen, bind strongly to the similar sites in hVKOR via both hydrogen and van der Waals bonding; particularly with Cys135. Thus, it interrupted the vitamin K reducing electron transfer pathway. Further, molecular dynamic (MD) simulation study revealed that the interactions of the ligands with hVKOR are stable. In conclusion, our analysis shed a light on the molecular mechanism of acetaminophen-induced coagulopathy previously reported in some clinical cases with chronic acetaminophen use. Furthermore, considering the anti-coagulopathy of NAPQI and NAC but not acetaminophen, the BBB permeation potency of these agents, and the risk of coagulopathy in COVID-19, we suggest a regular prothrombin time (PT) and INR monitoring of these patients taking acetaminophen and/or NAC.Communicated by Ramaswamy H. Sarma.

In Silico Investigation of the SARS CoV2 Protease with Thymoquinone, the Major Constituent of Nigella Sativa.

INTRODUCTION: The COVID-19 caused by a new type of coronavirus has emerged from China and led to thousands of deaths globally. Despite many groups engaged in studying the newly emerged virus and searching for the treatment, the understanding of the SARS-CoV2 target ligand interactions represents a key challenge. Several studies are being conducted to identify potential treatment. Alternatively, the results of numerous studies have shown that protease inhibitors can be a genuine leader in research. The antiviral activity and beneficial effect against respiratory disorders of thymoquinone have been largely demonstrated. AIM: The aim of this study is to evaluate in silico the inhibition of the replication of SARS CoV2 by thymoquinone. METHODS: This is a molecular simulation study using SARS CoV2 protease and thymoquinone structures provided by Protein Data Bank. RESULTS: The preliminary results have shown that thymoquinone may have inhibitory activities against SARS CoV2 protease. CONCLUSION: Furthermore, given the demonstrated results of thymoquinone, we can conclude that it may be considered as an effective or adjuvant treatment for SARS CoV2 infection.