In-silico analyses of naturally-occurring isoflavones as inhibitors of acetylcholinesterease

The most common kind of dementia is related to the Alzheimer disorder. In Colombia, the prevalence of dementia cases is ca.1.3% among people over 50 years old involving a greater load of mental disorders compared to other countries [1]. One of the most promising approaches within the treatment of the early stages of Alzheimer disease (and other dementia cases) is acetylcholinesterase (ACE) inhibitors-based therapy [2]. However, the efficacy of approved drugs has several limitations, being necessary the searching and evaluating additional biologically active compounds that have increased effectiveness in inhibiting the ACE enzyme. There is evidence that some naturally-occurring isoflavones may affect the cholinergic system of the brain and reduce the cognition deterioration [3]. Therefore, a group of 100 isoflavones obtained from plants of the family Fabaceae were assessed at in silico-level through molecular docking and molecular dynamics to identify those molecules that have higher affinity for the target enzyme (i.e., ACE). Once some isoflavone-related molecules were identified as promising at in-silico level, they were evaluated by means of an in-vitro ACE enzyme inhibition assay in order to validate the in-silico data. Thus, a CoMFA model was additionally constructed in order to establish the structure-activity and structure-affinity relationships for the test compounds obtaining a good model (R²= 0.721) for describing and predicting activity. For the most-stable isoflavone-enzyme complexes, a detailed structural interactions analysis and their relevance were also accomplished. Moreover, affinity and IC₅₀ values were correlated through multivariate statistical analysis, demonstrating good classification of isoflavones. The relationship between affinity, enzyme-inhibition activity and isoflavone-type was therefore described. This approach let us to propose 4 hit isoflavone-related structures as promising ACE inhibitors, with the purpose of contributing to the discovery and development of potential agents for Alzheimer disease therapy.

Acknowledgements: The present work is a product derived by the Project INV-CIAS-2050 financed by Vicerrectoría de Investigaciones at UMNG – Validity 2016.

Keywords: Acetylcholinesterase, isoflavones, docking, dynamics, QSAR.

References:

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