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Nowadays, the importance of computational methods in the design of therapeutic agents in a more efficient way is indisputable. Particularly, these methods have been important in the design of novel acetylcholinesterase enzyme inhibitors related to Alzheimer's disease. In this sense, in this report a computational model of linear prediction of acetylcholinesterase inhibitory activity of steroids and triterpenes is presented. The model is based in a correlation between binding energies obtained from molecular dynamic simulations (after docking studies) and [Formula: see text] values of a training set. This set includes a family of natural and semi-synthetic structurally related alkaloids reported in bibliography. These types of compounds, with some structural complexity, could be used as building blocks for the synthesis of many important biologically active compounds Therefore, the present study proposes an alternative based on the use of conventional and easily accessible tools to make progress on the rational design of molecules with biological activity.

The investigation of natural products in medicinal chemistry is essential today. In this context, acetylcholinesterase (AChE) inhibitors comprise one type of the compounds most actively studied in the search for an effective treatment of symptoms of Alzheimer's disease. This work describes the isolation of a natural compound, solanocapsine, the preparation of its chemical derivatives, the evaluation of AChE inhibitory activity, and the structure-activity analysis of relevant cases. The influence of structural variations on the inhibitory potency was carefully investigated by modifying different reactive parts of the parent molecule. A theoretical study was also carried out into the binding mode of representative compounds to the enzyme through molecular modeling. The biological properties of the series were investigated. Through this study valuable information was obtained of steroidal alkaloid-type compounds as a starting point for the synthesis of AChE inhibitors., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Alzheimer's dementia is a neurodegenerative disease that affects the elderly population and causes memory impairment and cognitive deficit. Manifestation of this disease is associated to acetylcholine decrease; thus, Cholinesterase inhibition is the main therapeutic strategy for the treatment of Alzheimer's disease. In the present study, a series of aporphinoid alkaloids were tested as potential acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors in vitro. Alkaloids liriodenine (3) and cassythicine (10) were the best inhibitors of both cholinesterases with IC50 values lower than 10 Î?M. In addition, these alkaloids demonstrated better inhibition of BChE than reference drug galantamine. In addition, some alkaloids showed selective inhibition. Laurotetatine clorhydrate (13) selectively inhibit AChE over BChE. On the contrary, pachyconfine (7) interacted more efficiently with BChE active site. Molecular modelling studies were performed in order to illustrate key interactions between most active compounds and the enzymes and to explain their selectivity. These studies reveal that the benzodioxole moiety exhibits strong interactions due to hydrogen bonds that form with the Glu201 (AChE) and Tyr440 (BChE) residues, which is reflected in the IC50 values. [ABSTRACT FROM AUTHOR]

[Display omitted] • Synthesis of cholinesterase inhibitors, fusing tacrine and the alkaloid solanocapsine. • Inhibition against AChE and BuChE enzymes at nM range was achieved. • Improved inhibition of BuChE was achieved since it could better allocate big compounds. • Docking and molecular dynamic studies suggest that they could act as dual inhibitors. To date, Alzheimer's disease is the most alarming neurodegenerative disorder worldwide. This illness is multifactorial in nature and cholinesterase inhibitors have been the ones used in clinical treatments. In this context, many of these drugs selectively inhibit the acetylcholinesterase enzyme interacting in both the active site and the peripheric anionic site. Besides, some agents have exhibited extensive benefits being able to co-inhibit butyrylcholinesterase. In this contribution, a strategy previously explored by numerous authors is reported; the synthesis of hybrid cholinesterase inhibitors. This strategy uses a molecule of recognized high inhibitory activity (tacrine) together with a steroidal alkaloid of natural origin using different connectors. The biological assays demonstrated the improvement in the inhibitory activity compared to the alkaloidal precursor, together with the reinforcement of the interactions in multiple sites of the enzymatic cavity. This strategy should be explored and exploited in this area. Docking and molecular dynamic studies were performed to explain enzyme-ligand interactions, assisting a structure–activity relationship analysis. [ABSTRACT FROM AUTHOR]