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Characterization of...
Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor
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- Kuang, Guanglin (författare)
- KTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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- Zhou, Yang, 1986- (författare)
- KTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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- Zou, Rongfeng (författare)
- KTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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- Halldin, C. (författare)
- Karolinska Institutet,Karolinska Inst, Ctr Psychiat Res, Dept Clin Neurosci, S-17176 Stockholm, Sweden.
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- Nordberg, A. (författare)
- Karolinska Institutet,Karolinska Univ Hosp, Ctr Alzheimer Res Translat Alzheimer Neurobiol, Dept Neurobiol Care Sci & Soc, S-14186 Huddinge, Sweden.
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- Långström, Bengt (författare)
- Uppsala universitet,Organisk kemi
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- Ågren, Hans (författare)
- KTH,Teoretisk kemi och biologi,Siberian Federal University, Russian Federation,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.;Siberian Fed Univ, Inst Nanotechnol Spect & Quantum Chem, Svobodny Pr 79, Krasnoyarsk 660041, Russia.
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- Tu, Yaoquan (författare)
- KTH,Teoretisk kemi och biologi,Royal Inst Technol KTH, AlbaNova Univ Ctr, Sch Biotechnol, Div Theoret Chem & Biol, S-10691 Stockholm, Sweden.
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(creator_code:org_t)
- 2017
- 2017
- Engelska.
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Ingår i: RSC Advances. - : Royal Society of Chemistry. - 2046-2069. ; 7:32, s. 19787-19793
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- The α7 nicotinic acetylcholine receptor (α7-nAChR) is assumed to be implicated in a variety of neurological disorders, such as schizophrenia and Alzheimer's disease (AD). The progress of these disorders can be studied through imaging α7-nAChR with positron emission tomography (PET). [18F]ASEM is a novel and potent α7-nAChR PET radioligand showing great promise in recent tests. However, the mechanism of the molecular interaction between [18F]ASEM and α7-nAChR is still unclear. In this paper, the binding profile of [18F]ASEM to a chimera structure of α7-nAChR was investigated with molecular docking, molecular dynamics, and metadynamics simulation methods. We found that [18F]ASEM binds at the same site as the crystallized agonist epibatidine but with a different binding mode. The dibenzo[b,d]thiophene ring has a different orientation compared to the pyridine ring of epibatidine and has van der Waals interactions with residues from loop C on one side and π-π stacking interaction with Trp53 on the other side. The conformation of Trp53 was found to have a great impact on the binding of [18F]ASEM. Six binding modes in terms of the side chain dihedral angles χ1 and χ2 of Trp53 were discovered by metadynamics simulation. In the most stable binding mode, Trp53 adopts a different conformation from that in the crystalline structure and has a rather favorable π-π stacking interaction with [18F]ASEM. We believe that these discoveries can be valuable for the development of novel PET radioligands.
Ämnesord
- NATURVETENSKAP -- Kemi (hsv//swe)
- NATURAL SCIENCES -- Chemical Sciences (hsv//eng)
Nyckelord
- Binding energy
- Dihedral angle
- Molecular dynamics
- Neurodegenerative diseases
- Positron emission tomography
- Van der Waals forces
- Alzheimer's disease
- Crystalline structure
- Metadynamics simulations
- Molecular docking
- Neurological disorders
- Nicotinic acetylcholine receptors
- Positron emission tomography (PET)
- Van Der Waals interactions
- Bins
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