Thein silicomechanism of hVKOR interaction with acetaminophen and its metabolite, as well as N-acetyl cysteine: caution on application in COVID-19 patients

Abstract

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

Molecular Analysis of KPC and GES Beta-Lactamase Genes in Clinical Isolates of Klebsiella pneumoniae by PCR Method

“…K. pneumoniae has been widely distributed in hospitals and known as an opportunistic bacterium for developing various types of nosocomial infections in hospitalized patients [19,35,36]. Antimicrobial resistance complicated the treatment of infections related to K. pneumoniae.…”

Home pharmacological therapy in early COVID‐19 to prevent hospitalization and reduce mortality: Time for a suitable proposal

“…131 Celecoxib is able to directly target SARS-CoV2 and block its activity, 112 an evidence that can explain why patients using celecoxib and other NSAIDs more than acetaminophen in the early symptoms of COVID-19, had the lowest risk of being hospitalized. 18,132 The use of NSAIDs in home therapy against COVID-19 was not so widespread and counselled as due, in order to prevent disease worsening. The panel of NSAIDs is particularly enriched of novel therapeutic drugs, which could successfully address COVID-19 in its early phases.…”

“…111 Selective inhibitors of COX-2, which are currently used in clinics, such as the sulphonamide celecoxib and the methylsulphone etoricoxib, have been reported as capable of reducing significantly COVID-19 patients' hospitalization rate. 18 Many of these pharmaceuticals are endowed with an anti-viral activity. 112 Indomethacin is another NSAID, which was effective against the first SARS coronavirus in the outbreak of more than 15 years ago.…”

“…This engulfed a huge need of medical expertise and caregivers, often subtracting people from having an available consultancy at home or at their disposal. In this perspective, suggestions and recommendations were even reported elsewhere in the literature, 1,4 despite some critical comment 17–20 . The fundamental role of a home protocol to address mild COVID‐19 or the early symptoms of this pathology is to ensure a rapid pharmacological intervention in order to absolutely prevent hospitalization, often due to exacerbation more than excessive caution.…”

“…In this perspective, suggestions and recommendations were even reported elsewhere in the literature, 1,4 despite some critical comment. [17][18][19][20] The fundamental role of a home protocol to address mild COVID-19 or the early symptoms of this pathology is to ensure a rapid pharmacological intervention in order to absolutely prevent hospitalization, often due to exacerbation more than excessive caution. In this sense, therapeutic drugs must be promptly available, easy to be provided and able to target the first steps leading to the etiopathogenesis of COVID-19.…”