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J Mol Model. 2018 Aug 18;24(9):243. doi: 10.1007/s00894-018-3790-9.

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

Wang Y1,2,3,4,5,6,7, Lin W1,2,3,4, Wu N1,2,3,4, He X1,2,3,4, Wang J1,2,3,4, Feng Z8,9,10,11, Xie XQ12,13,14,15.

Author information

1
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
2
National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
3
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
4
Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
5
School of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
6
Chongqing Key Laboratory of Medicinal Chemistry and Molecular Pharmacology, Chongqing, 400054, China.
7
Chongqing Key Laboratory of Target Based Drug Screening and Effect Evaluation, Chongqing, 400054, China.
8
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA. zhf11@pitt.edu.
9
National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15261, USA. zhf11@pitt.edu.
10
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA. zhf11@pitt.edu.
11
Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. zhf11@pitt.edu.
12
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261, USA. xix15@pitt.edu.
13
National Center of Excellence for Computational Drug Abuse Research, University of Pittsburgh, Pittsburgh, PA, 15261, USA. xix15@pitt.edu.
14
Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA. xix15@pitt.edu.
15
Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15261, USA. xix15@pitt.edu.

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. Graphical abstract Paracetamol and its metabolites.

KEYWORDS:

Acetaminophen; CB1; Drug abuse; Overdose; TRPA1; TRPV1

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