6FLD

Carbamylated T. californica acetylcholineterase bound to uncharged hybrid reactivator 1

Summary for 6FLD

• Entry DOI: 10.2210/pdb6fld/pdb
• Descriptor: Acetylcholinesterase, 2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[(~{E})-hydroxyiminomethyl]-6-[4-(1,2,3,4-tetrahydroacridin-9-ylamino)butyl]pyridin-3-ol, ... (7 entities in total)
• Functional Keywords: acetylcholinesterase hybrid reactivators organophosphate inhibition structure-based optimization, hydrolase
• Biological source: Tetronarce californica (Pacific electric ray)
• Total number of polymer chains: 1
• Total formula weight: 61948.95

Authors

De la Mora, E.,Santoni, G.,de Souza, J.,Sussman, J.,Silman, I.,Baati, R.,Weik, M.,Nachon, F. (deposition date: 2018-01-25, release date: 2018-08-29, Last modification date: 2020-07-29)

Primary citation

Santoni, G.,de Sousa, J.,de la Mora, E.,Dias, J.,Jean, L.,Sussman, J.L.,Silman, I.,Renard, P.Y.,Brown, R.C.D.,Weik, M.,Baati, R.,Nachon, F.
Structure-Based Optimization of Nonquaternary Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents.
J. Med. Chem., 61:7630-7639, 2018

PubMed Abstract: Acetylcholinesterase (AChE), a key enzyme in the central and peripheral nervous systems, is the principal target of organophosphorus nerve agents. Quaternary oximes can regenerate AChE activity by displacing the phosphyl group of the nerve agent from the active site, but they are poorly distributed in the central nervous system. A promising reactivator based on tetrahydroacridine linked to a nonquaternary oxime is also an undesired submicromolar reversible inhibitor of AChE. X-ray structures and molecular docking indicate that structural modification of the tetrahydroacridine might decrease inhibition without affecting reactivation. The chlorinated derivative was synthesized and, in line with the prediction, displayed a 10-fold decrease in inhibition but no significant decrease in reactivation efficiency. X-ray structures with the derivative rationalize this outcome. We thus show that rational design based on structural studies permits the refinement of new-generation pyridine aldoxime reactivators that may be more effective in the treatment of nerve agent intoxication.

PubMed: 30125110
DOI: 10.1021/acs.jmedchem.8b00592

Experimental method

X-RAY DIFFRACTION (2.4 Å)