Characterization of the binding mode of the PET tracer [18F]ASEM to a chimera structure of the α7 nicotinic acetylcholine receptor

• 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

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