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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

Hashemi et al., Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1910570
Apr 2021  
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2nd treatment shown to increase risk in November 2020
 
*, now with p = 0.00000029 from 27 studies, but still recommended in 64 countries.
* From meta analysis with ≥3 studies.
4,800+ studies for 102 treatments. c19early.org
In Silico study suggesting increased risk of cerebral hemorrhage with acetaminophen use for COVID-19. Authors show acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI), and to a lesser extent N-acetylcysteine (NAC), bind to human vitamin K epoxide reductase (hVKOR), interrupting the vitamin K reducing electron transfer pathway. Authors suggest that this may explain previous clinical reports of coagulopathy with chronic acetaminophen use, and considering the risk of coagulopathy in COVID-19, they recommend monitoring prothrombin time and international normalized ratio in COVID-19 patients taking acetaminophen and/or NAC.
Acetaminophen is also known as paracetamol, Tylenol, Panadol, Calpol, Tempra, Calprofen, Doliprane, Efferalgan, Grippostad C, Dolo, Acamol, Fevadol, Crocin, and Perfalgan.
Study covers acetaminophen and N-acetylcysteine.
Hashemi et al., 20 Apr 2021, peer-reviewed, 3 authors. Contact: zbatha2000@yahoo.com, bathai_z@modares.ac.ir.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperAcetaminophenAll
Thein silicomechanism of hVKOR interaction with acetaminophen and its metabolite, as well as N-acetyl cysteine: caution on application in COVID-19 patients
S Ali Hashemi, Armita Kyani, S Zahra Bathaie
Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1910570
Acetaminophen and N-acetyl cysteine (NAC) are being used as supportive care in patients suffering from coronavirus disease 2019 . 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.
Disclosure statement The authors claim that there is no conflict of interest.
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