Inhibition of acetylcholinesterase by physostigmine analogs: Conformational mobility of cysteine loop due to the steric effect of the alkyl chain

The effect of a series of physostigmine analogs on acetylcholinesterase activity was investigated. The second‐order rate constant kon of the enzyme–inhibitor complex correlates with the conformational positioning of aromatic residues, especially Trp84, in the transition state complex. The van der Waals interactions are an important structural element of this conformational change. A transient mobility of the cysteine loop (Cys67–Cys94) was confined only to the presence of a significant steric effect. Even with this limitation, however, the steric effect seems to be an appropriate model for future tests on the “back door” hypothesis involving facilitated opening for faster product clearance. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:64–69, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/jbt.10026