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. 2012 Apr;5(4):1043-8.
doi: 10.3892/mmr.2012.757. Epub 2012 Jan 17.

Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution

Po-Yuan Chen  1 , Ching-Tsan Tsai, Che-Yen Ou, Wei-Tse Hsu, Mien-De Jhuo, Chieh-Hsi Wu, Tzu-Ching Shih, Tzu-Hurng Cheng, Jing-Gung Chung
Affiliations

Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution

Po-Yuan Chen et al. Mol Med Rep. 2012 Apr.

Abstract

Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments.

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Figures

Figure 1
Figure 1
Conformation of Evo27 in the binding site, in triple bonds will form a hydrophobic interactions, and hook the buttom of the tunnel. In the median of tunnel OH base of Evo27 f H-bond is formed with the residue Trp121, and an extended side chain also produces good performance at the top.
Figure 2
Figure 2
Conformation of Evo9 in the binding site; Evo9 forms H-bonds with the residue Trp121 and Tyr338. Benzyl group formulates ring aromatic group and five rings of that formulate hydrophobic interaction.
Figure 3
Figure 3
The principal structure of Evo27 and Evo9 express the same docking pose, but other side chains provide adequate interaction. Green, Evo27; blue, Evo9.
Figure 4
Figure 4
Illustration of the ligand binding of side atoms. Benzyl group of Com1 to form π-π stacking in the middle, and piperidinic nitrogen can form cation-π interaction with residue Trp283.
Figure 5
Figure 5
Illustration of the ligand binding side atoms. In the middle, benzyl group of Com7 forms π-π stacking interactions with the top and bottom.
Figure 6
Figure 6
Evo27, Evo9, Com7 and Com1 perform ADMET tools. 2D ADMET Plot shows that Com7 and Com1 are in the 95 and 99% blood brain barrier (BBB) confidence ellipse region.
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References

    1. Dorronsoro C, Barbero S, Llorente L, Marcos S. On-eye measurement of optical performance of rigid gas permeable contact lenses based on ocular and corneal aberrometry. Optom Vis Sci. 2003;80:115–125. - PubMed
    1. Guo T, Hobbs DW. Development of BACE1 inhibitors for Alzheimer's disease. Curr Med Chem. 2006;13:1811–1829. - PubMed
    1. Wood KE, Becker BN, McCartney JG, D'Alessandro AM, Coursin DB. Care of the potential organ donor. N Engl J Med. 2004;351:2730–2739. - PubMed
    1. Jacobsen JS, Reinhart P, Pangalos MN. Current concepts in therapeutic strategies targeting cognitive decline and disease modification in Alzheimer's disease. NeuroRx. 2005;2:612–626. - PMC - PubMed
    1. Mori F, Fukaya M, Abe H, Wakabayashi K, Watanabe M. Developmental changes in expression of the three ryanodine receptor mRNAs in the mouse brain. Neurosci Lett. 2000;285:57–60. - PubMed

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