An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation

Yuanqiang Wang, Weiwei Lin, Nan Wu, Xibing He, Junmei Wang, Zhiwei Feng, Xiang Qun Xie

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Paracetamol is a relatively safe analgesia/antipyretic drug without the risks of addiction, dependence, tolerance, and withdrawal when used alone. However, when administrated in an opioid/paracetamol combination product, which often contains a large quantity of paracetamol, it can be potentially dangerous due to the risk of hepatotoxicity. Paracetamol is known to be metabolized into N-(4-hydroxyphenyl)-arachidonamide (AM404) via fatty acid amide hydrolase (FAAH) and into N-acetyl-p-benzoquinone imine (NAPQI) via cytochrome P450 (CYP) enzymes. However, the underlying mechanism of paracetamol is still unclear. In addition, paracetamol has the potential to interact with other drugs that are also involved with CYP family enzymes (inducer/inhibitor/substrate), an example being illicit drugs. In our present work, we looked into the relationship between paracetamol and its metabolites (AM404 and NAPQI) using molecular docking and molecular dynamics (MD) simulations. We first carried out a series of molecular docking studies between paracetamol/AM404/NAQPI and their reported targets, including CYP 2E1, FAAH, TRPA1, CB1, and TRPV1. Subsequently, we performed MD simulations and energy decomposition for CB1-AM404, TRPV1-AM404, and TRPV1-NAPQI for further investigation of the dynamics interactions. Finally, we summarized and discussed the reported drug–drug interactions between paracetamol and central nervous system drugs, especially illicit drugs. Overall, we are able to provide new insights into the structural and functional roles of paracetamol and its metabolites that can inform the potential prevention and treatment of paracetamol overdose. [Figure not available: see fulltext.].

Original languageEnglish (US)
Article number243
JournalJournal of Molecular Modeling
Volume24
Issue number9
DOIs
StatePublished - Sep 1 2018
Externally publishedYes

Fingerprint

metabolites
Acetaminophen
Metabolites
Molecular dynamics
drugs
molecular dynamics
cytochromes
Hydrolases
quinones
imines
Computer simulation
Amides
Fatty acids
fatty acids
simulation
amides
enzymes
analgesia
Imines
Neurology

Keywords

  • Acetaminophen
  • CB1
  • Drug abuse
  • Overdose
  • TRPA1
  • TRPV1

ASJC Scopus subject areas

  • Catalysis
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Computational Theory and Mathematics
  • Inorganic Chemistry

Cite this

An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation. / Wang, Yuanqiang; Lin, Weiwei; Wu, Nan; He, Xibing; Wang, Junmei; Feng, Zhiwei; Xie, Xiang Qun.

In: Journal of Molecular Modeling, Vol. 24, No. 9, 243, 01.09.2018.

Research output: Contribution to journalArticle

Wang, Yuanqiang ; Lin, Weiwei ; Wu, Nan ; He, Xibing ; Wang, Junmei ; Feng, Zhiwei ; Xie, Xiang Qun. / An insight into paracetamol and its metabolites using molecular docking and molecular dynamics simulation. In: Journal of Molecular Modeling. 2018 ; Vol. 24, No. 9.
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