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Nicotine Enantioselectively Targets Myeloid Differentiation Protein 2 and Inhibits the Toll-like Receptor 4 Signaling.
- Source :
-
Journal of chemical information and modeling [J Chem Inf Model] 2024 Jul 08; Vol. 64 (13), pp. 5253-5261. Date of Electronic Publication: 2024 Jun 18. - Publication Year :
- 2024
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Abstract
- Psychoactive substances, including morphine and methamphetamine, have been shown to interact with the classic innate immune receptor Toll-like receptor 4 (TLR4) and its partner protein myeloid differentiation protein 2 (MD2) in a nonenantioselective manner. (-)-Nicotine, the primary alkaloid in tobacco and a key component of highly addictive cigarettes, targets the TLR4/MD2, influencing TLR4 signaling pathways. Existing as two enantiomers, the stereoselective recognition of nicotine by TLR4/MD2 in the context of the innate immune response remains unclear. In this study, we synthesized (+)-nicotine and investigated its effects alongside (-)-nicotine on lipopolysaccharide (LPS)-induced TLR4 signaling. (-)-Nicotine dose-dependently inhibited proinflammatory factors such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and cyclooxygenase-2 (COX-2). In contrast, (+)-nicotine showed no such inhibitory effects. Molecular dynamics simulations revealed that (-)-nicotine exhibited a stronger affinity with the TLR4 coreceptor MD2 than (+)-nicotine. Additionally, in silico simulations revealed that both nicotine enantiomers initially attach to the entrance of the MD2 cavity, creating a metastable state before they fully enter the cavity. In the metastable state, (-)-nicotine established more stable interactions with the surrounding residues at the entrance of the MD2 cavity compared to those of (+)-nicotine. This highlights the crucial role of the MD2 cavity entrance in the chiral recognition of nicotine. These findings provide valuable insights into the distinct interactions between nicotine enantiomers and the TLR4 coreceptor MD2, underscoring the enantioselective effect of nicotine on modulating TLR4 signaling.
- Subjects :
- Stereoisomerism
Humans
Lipopolysaccharides pharmacology
Molecular Docking Simulation
Cyclooxygenase 2 metabolism
Cyclooxygenase 2 chemistry
Toll-Like Receptor 4 metabolism
Nicotine pharmacology
Nicotine chemistry
Nicotine analogs & derivatives
Nicotine metabolism
Lymphocyte Antigen 96 metabolism
Lymphocyte Antigen 96 chemistry
Signal Transduction drug effects
Molecular Dynamics Simulation
Subjects
Details
- Language :
- English
- ISSN :
- 1549-960X
- Volume :
- 64
- Issue :
- 13
- Database :
- MEDLINE
- Journal :
- Journal of chemical information and modeling
- Publication Type :
- Academic Journal
- Accession number :
- 38973303
- Full Text :
- https://doi.org/10.1021/acs.jcim.4c00591