Affinity Selection-Mass Spectrometry for the Identification of Ligands of Acetylcholinesterase from Topsentia ophiraphidites and Docking Studies for the Dereplicated Ligands

TL;DR

This study identifies potential acetylcholinesterase ligands from a sponge species and uses docking to explore their interactions, offering new leads for Alzheimer's research.

Contribution

The study reports novel AChE ligands from Topsentia ophiraphidites and their docking analysis for drug discovery.

Findings

Four compounds were identified as AChE ligands with affinity ratios between 1.20 and 1.84.

Molecular docking revealed that the (R, R) stereoisomer of one compound interacts strongly with AChE's active site.

The ligands show potential for further pharmacological investigation.

Abstract

Acetylcholinesterase (AChE) inhibition has been successful
for
the treatment of Alzheimer’s disease and still stands as an
important target in the search for novel ligands. In this context,
affinity selection-mass spectrometry (AS-MS) has been acknowledged
as a high-throughput screening (HTS) technique for large molecular
libraries in drug discovery programs and natural product investigations.
In this work, an AS-MS assay with AChE immobilized onto magnetic beads
(AChE-MB) has been used to search for ligands in samples of the sponge Topsentia ophiraphidites collected in the archipelago
of Fernando de Noronha, Brazil. Ligand dereplication disclosed 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin
A, 3,5-dibromo-O-methyltyrosine, 3-bromo-5-iodo-O-methyltyrosine, and 3,5-di-iodo-O-methyltyrosine
as AChE ligands, which showed affinity ratios of 1.84, 1.34, 1.26,
and 1.20, respectively, in the AS-MS assay. As a complementary approach,
molecular docking analysis with human AChE has been carried out for
the disclosed dereplicated ligands, in which the (R, R) stereoisomer of 6-desmethyl-6-ethyl-9,10-dihydrospongosoritin
A stood out, performing important intermolecular interactions with
the active sites of AChE, especially with the peripheral anionic site,
at the entrance of the gorge. The results stimulate further investigations
of these ligands in other pharmacological assays in order to better
understand their mechanisms of action.

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