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Evaluation of Amaryllidaceae alkaloids as inhibitors of human acetylcholinesterase by QSAR analysis and molecular docking

Andrés López,O. M. M. Martínez,Héctor Fabio Cortés Hernández

Published 2021 in Journal of Molecular Structure

ABSTRACT

Abstract There currently are a large number of natural products of plant origin that have potential use in the treatment of Alzheimer's disease. One of the most commonly used drugs for the treatment of this disease contains the galantamine alkaloid isolated from amaryllidine plants as an active ingredient, whose action lies in the inhibition of acetylcholinesterase (AChE). For this reason, it is promising to evaluate other alkaloids from this family of plants. In the present investigation, the inhibitory activity of human AChE by alkaloids of amaryllidic species registered in the PubChem and Reaxys chemical databases was evaluated through the development of 4 qualitative QSAR models. The models were based on the random forest algorithm using the calculated descriptors in Volsurf + and DRAGON of compounds that had reported AChE inhibitory activity in the ChEMBL and NPASS databases. From the QSAR models, 11 alkaloids with the highest inhibitory potential were obtained. Molecular docking analysis was used to examine the interactions of these 11 alkaloids with various residues of the protein active site. Overall, 23 representative descriptors were reported whose interpretation allowed to identify several properties that confer inhibitory potential against human AChE, in fact, the presence of amine groups, hydroxyl groups and aromatic rings in fused cycles are able to shape prolated and planar geometries are significant for hydrogen bond and aromatic stacking interactions in the active site of human AChE. Among the 11 alkaloids founded, lycoramine showed the highest inhibitory potential, and masonine presented interactions in the CAS (Catalytic Anionic Site) and PAS (Peripheral Anionic Site). Therefore, these compounds could be potential unconventional inhibitors of AChE.

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