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Alzheimer Disease Drugs Against AChE

Alzheimer Disease Drugs Against AChE

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Published by Ponne Saravanan

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Published by: Ponne Saravanan on Jul 19, 2012
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Prof. R. Boopathy Director School of Biotechnology and Genetic Engineering Bharathiar University, Coimbatore – 641 046 boopathybiotech@yahoo.


Our team research: Identification of peptides that could interact with AChE and its relevance Slide 20 to . What is known and relevant to the workshop? (A Birds’ Eye View) Slide 3 to 10 2.Acetylcholinesterase Potential directions of research for pesticide poisoning 1. Why not AD drugs as antidote on OP poisoning? Slide 11 to 19 3.


Why not AD drugs as antidote on OP poisoning? .

. (2002) Biochemistry Vol 41. Competitive Reversible.Alzheimer Disease Drugs against AChE Name of the drug Donepezil1 Huperzine2 Tacrine3 Nature of the drug N-benzyl piperidine based compound Alkaloid Amino acridine compound Carbamate Type of Inhibition Reversible. 321-326 5Bar-on et al. 297-306 2Dvir et al. Noncompetitive Reversible. (1999) Structure Vol 7.48 μM competitive *As reported for human AChE in the BRENDA enzyme database 1Kryger et al.. Noncompetitive Reversible.. No 3. 9031-9035 4Greenblatt et al. (1999) FEBS Letters Vol 463. (2002) Biochemistry Vol 41. Non.. 3555-3564 . Competitive IC50* 22 nM > 47 nM 190 nM 800 nM Galanthamine4 Alkaloid Rivastigmine5 Pseudo-irreversible. 10810-10818 3Harel et al. (1993) PNAS Vol 90..

Mode of action of Donepezil • Occupies the catalytic and peripheral anionic site • No direct interaction with the catalytic site * DIMETHOXYINDANONE MOIETY PIPERIDINE MOIETY BENZYL MOIETY Binds to the PAS site residue Trp279 Cation-Π stacking with Phe330 Oriented towards CA site Π-Π stacking with Trp84 * Mode of drug binding with Torpedo AChE .

Mode of action of Huperzine * • Disruption of bond between Gly117-Gly118 and formation of new bonds by Gly117 with Gly119 and Ala201 H-bond with His440 Repels G117 carbonyl carbon (Carbonyl-carbonyl repulsion) * Mode of drug binding with Torpedo AChE .

Mode of action of Tacrine • Π-Π stacking of acridine against Trp84 * H-bonding with His440 * Mode of drug binding with Torpedo AChE .

Mode of action of Galantamine * • Binds to choline binding site (Trp84) and acyl binding pocket (Phe288 & Phe290) H-bond with Glu199 Binds with Ser200 Cation-Π stacking with Trp84 H-bond with Asp72 * Mode of drug binding with Torpedo AChE .

Mode of action of Rivastigmine * • Carbamyl moiety linked covalently to Ser200 • Disruption of catalytic triad: H440 moves away from E327 • Part of inhibitor occupies peripheral anionic site (Trp84. Phe330 H-bonding with Gly118 . Phe330) CARBAMYL GROUP H-bonding with Gly119 & Ala201 Covalent linkage with Ser200 * Mode of drug binding with Torpedo AChE S-3[1-(DIETHYL AMINO)ETHYL]PHENOL GROUP Π-Π stacking with Trp84.

35(1):85-92.. 1989 Jan.3 mg/kg). finally paralysis and death occurs. Under conditions where AChE completely lost its enzyme activity due to DFP treatment. AChE pretreated with Tacrine retained 60% of its activity. Ref: Wu et al. • It combines with the amino acid serine at the active site of the enzyme acetylcholinesterase inactivating it.Can AD drugs be used as antidote? The story of DFP • Diisopropyl fluorophosphate (DFP) is a stable organophosphorus insecticide. • DFP is a very potent neurotoxin (LD50 in rats is 1. . Mol Pharmacol.

Ref: Mamczarz et al. • When pretreated with Galantamine.32(6):785-98. .Can AD drugs be used as antidote? The story of Soman • Soman is an extremely toxic chemical substance. Neurotoxicology. It is a nerve agent inhibiting the cholinesterase enzyme.. Galantamine prevents both the acute toxicity and the delayed cognitive deficits triggered by soman poison and can be used against other organophosphorous compounds. Epub 2011 Jul 19. 2011 Dec. the soman exposed guinea pigs showed no learning impairment and no memory retention deficit.

Identification of peptides that have interaction with AChE .

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