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. 2011 May 1;21(9):2687-91.
doi: 10.1016/j.bmcl.2010.12.041. Epub 2010 Dec 16.

(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase

Ziyad F Al-Rashid  1 , Richard P Hsung
Affiliations

(+)-Arisugacin A--computational evidence of a dual binding site covalent inhibitor of acetylcholinesterase

Ziyad F Al-Rashid et al. Bioorg Med Chem Lett. .

Abstract

A computation docking study of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. The model suggests that (+)-arisugacin A is a dual binding site covalent inhibitor of AChE. These findings are examined in the context of Alzheimer's disease-modifying therapeutic design. (+)-Arisugacin A's revealed mode of action is unique, and may serve as a basis for the development of AD therapeutics capable of treating the symptomatic aspects of AD, while being neuroprotective with long term efficacy.

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Figures

Figure 1
Figure 1
Five AChE inhibitors approved as therapeutic drugs for combating dementia, and (+)-arisugacin A.
Figure 2
Figure 2
The binding and active site of AChE.
Figure 3
Figure 3
Total synthesis of (+)-arisugacin A.
Figure 4
Figure 4
Established SARs for arisugacin-related territrem B.
Figure 5
Figure 5
Potential for π-stacking by the CDE portion of (+)-arisugacin A.
Figure 6
Figure 6
Three major binding modes of (+)-arisugacin A at the active site of AChE: Mode-I [a]: 1st of 100 binding modes. Binding affinity = −11.8 kcal mol−1; Mode-II [b]: 2nd of 100 binding modes. Binding affinity = −10.7 kcal mol−1; Mode-III [c and d]: 3rd of 100 binding modes. Binding affinity = −10.4 kcal mol−1.
Figure 7
Figure 7
(+)-Arisugacin A-AChE interactions seen in docking Mode-III.
Figure 8
Figure 8
Close ups of Mode-III examining the vicinity of the catalytic triad (His440, Ser200, and Glu327) and Glu199 highlighted in orange.
Figure 9
Figure 9
Overlay of binding Mode-III of (+)-arisugacin A (green) and donepezil (yellow) bound to AChE.
See this image and copyright information in PMC

References

    1. Alzheimer A. Gesamte Psychiatrie. 1907;64:1264.

    1. For a census study on the prevalence of dimentia, see: Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, Hall K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, Rimmer E, Scazufca M. Lancet. 2005;366:2112.

    1. For general reviews on therapeutic treatment of Alzheimer's disease, see: Giacobini E. In: Cognitive Enhancing Drugs. Buccafusco JJ, editor. Basel–Boston–Berlin: Birkhauser; 2004. pp. 11–36. Giacobini E, Spiegel R, Enz A, Veroff AE, Cutler RE. J. Neural Transm. 2002;109:1053. Giacobini E, Becker R, editors. Alzheimer's Disease: From Molecular Biology to Therapy. Boston: Birkhauser; 1997. John V, Lieberburg I, Thorsett ED. Ann. Rep. Med. Chem. 1993;28:197.

    1. For a review of the Amyloid Hypothesis, see: Hardy J, Selkoe DJ. Science. 2002;297:353.

    1. For references on β-amyloid targeting, see: Melnikova I. Nat. Rev. Drug Discov. 2007;6:341. Skovronsky DM, Lee VM-Y, Trojanowski JQ. Annu. Rev. Pathol. Mech. Dis. 2006;1:151. Saido TC, Iwata N. Neurosci. Res. 2006;54:235.

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