Applications of Integrated Data Mining Methods to Exploring Natural Product Space for Acetylcholinesterase Inhibitors

Abstract

Nature, especially the plant kingdom, is a rich source for novel bioactive compounds that can be used as lead compounds for drug development. In order to exploit this resource, the two neural network-based virtual screening techniques novelty detection with self-organizing maps (SOMs) and counterpropagation neural network were evaluated as tools for efficient lead structure discovery. As application scenario, significant descriptors for acetylcholinesterase (AChE) inhibitors were determined and used for model building, theoretical model validation, and virtual screening. Top-ranked virtual hits from both approaches were docked into the AChE binding site to approve the initial hits. Finally, in vitro testing of selected compounds led to the identification of forsythoside A and (+)-sesamolin as novel AChE inhibitors.

In Silico‐Guided Strategies for the Discovery and Rationalization of Bioactive Natural Products

“…As different virtual screening tools can produce different virtual hit lists, the combination of various methods (e.g., ligand-and structure-based virtual screenings) can offer a complementary discovery of activities (Schuster et al, 2010b). Usually, virtual screening studies begin with the least-demanding approaches and progress to the more accurate, time-consuming techniques in the last stages, where fewer compounds remain to be investigated (Talevi, Gavernet, and Bruno-Blanch, 2009 …”

“…The generation of maps and thereby the visualization of the relationships between the objects is one of the most important advantages of this method. Schuster et al (2010b) applied two neural network-based virtual screening techniques (novelty detection and counterpropagation neural networks) to explore the NP space for acetylcholinesterase (AChE) inhibitors. This enzyme is involved in accelerating the assembly of β-amyloid into amyloid fibrils that are characteristically found in the brain cells of Alzheimer's patients.…”

Cholinergic Modulation by Opioid Receptor Ligands: Potential Application to Alzheimer's Disease

“…Continuing the study of AChEI based on the morphinan structural scaffold, Rollinger and colleagues described the use of molecular modeling approaches to rationally identify novel AChEI based on a synthetic morphinan-based pharmacophore [5, 58–59]. An initial screen of a natural products database identified several opiates present in P. somniferum that were predicted to inhibit AChE.…”

“…Galantamine was shown to engage in hydrogen bonding with Glu199 through its C-6 hydroxyl group and the 3-methyl ether accepts a hydrogen bond from Ser200 [59]. Evidence was also presented that a non-classic hydrogen bond between the N -methyl group of galantamine and an aspartate residue in the binding pocket can also occur.…”

Catechol alkenyls from Semecarpus anacardium: Acetylcholinesterase inhibition and binding mode predictions

“…The identification of natural compounds with AChE inhibitory activity in plants from traditional medicine can be supported by virtual screening (Rollinger et al, 2004;Schuster et al, 2010). The use of molecular modeling techniques in the field of AChE inhibitors is facilitated by the availability of AChE X-ray crystal structures with and without co-crystallized inhibitors.…”