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. 2013 Mar 4;18(3):2878-94.
doi: 10.3390/molecules18032878.

New tacrine analogs as acetylcholinesterase inhibitors - theoretical study with chemometric analysis

Paweł Szymański  1 , Robert Skibiński, Tadeusz Inglot, Marek Bajda, Jakub Jończyk, Barbara Malawska, Elżbieta Mikiciuk-Olasik
Affiliations

New tacrine analogs as acetylcholinesterase inhibitors - theoretical study with chemometric analysis

Paweł Szymański et al. Molecules. .

Abstract

Computer simulations constitute the basis of the design and discovery of new drugs. This approach is not only significant with regards to finding new structures, but also for selecting the molecules with the highest probability of being useful in the diagnostic process and treatment of numerous diseases. In our work, we used computational software to analyze 32 new acetylcholinesterase (AChE) inhibitors and formulate ADMET predictions. To understand the influence of the structure of our derivatives on binding mode, we docked all structures to the active site of AChE and assigned some pharmacophoric features. Finally, we undertook a chemometric analysis of all the compounds on the basis of FT-IR, which gave us the possibility of performing a fast categorization of the analyzed compounds and design compounds with similar structures.

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Figures

Figure 1
Figure 1
Analyzed compounds: tetrahydroacridine derivatives 1–8 and 17–24; cyclopenta[b]quinoline derivatives 9–16 and 25–32 [11,12,13,14,15,16].
Figure 2
Figure 2
Genotoxicity profile for analyzed compounds.
Figure 3
Figure 3
Visualization of the genotoxic properties for tacrine. Hazardous substructures (genotoxic fragments) are colored in red.
Figure 4
Figure 4
Different “hazardous” substructures were identified. Compounds with two carbon atoms in the chain from every group are presented.
Figure 5
Figure 5
CNS activity plot showing known CNS-penetrating (blue points) and peripherally acting drugs (red points). The green quadrates denote some currently analyzed molecules correctly classified by our model as CNS active for compound 19 or CNS inactive for compound 1.
Figure 6
Figure 6
The binding mode of compound 27 into the active site of acetylcholinesterase.
Figure 7
Figure 7
Pharmacophore model for the novel class of acetylcholinesterase inhibitors (meaning of colors: orange – aromatic feature, green – hydrophobic, pink – H-bond donor; radius of feature represents precision of assignment).
Figure 8
Figure 8
Principal component analysis (PCA) of ATR-FT-IR spectra of 32 analyzed AChE inhibitors.
Figure 9
Figure 9
The dendrogram obtained using Minkowski distance for ATR-FT-IR spectra of 32 analyzed AChE inhibitors.
See this image and copyright information in PMC

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