Structural basis of femtomolar inhibitors for acetylcholinesterase subtype selectivity: Insights from computational simulations

Acetylcholinesterase (AChE) is a key enzyme of the cholinergic nervous system. More than one gene encodes the synaptic AChE target. As the most potent known AChE inhibitor, the syn1-TZ2PA6 isomer was recently shown to have higher affinity as a reversible organic inhibitor of acetylcholinesterase1 (AChE1) than the anti1-TZ2PA6 isomer. Opposite selectivity has been shown for acetylcholinesterase2 (AChE2). In an attempt to understand the selectivity of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2, six molecular dynamics (MD) simulations were carried out with mouse AChE (mAChE, type of AChE1), Torpedo californica AChE (TcAChE, type of AChE1), and Drosophila melanogaster AChE (DmAChE, type of AChE2) bound with syn1-TZ2PA6 and anti1-TZ2PA6 isomers. Within the structure of the inhibitor, the 3,8-diamino-6-phenylphenanthridinium subunit and 9-amino-1,2,3,4-tetrahydroacridine subunit, via π–π interactions, made more favorable contributions to syn1-TZ2PA6 or anti1-TZ2PA6 isomer binding in the mAChE/TcAChE enzyme than the 1,2,3-triazole subunit. Compared to AChE1, the triazole subunit had increased binding energy with AChE2 due to a greater negative charge in the active site. The binding free energy calculated using the MM/PBSA method suggests that selectivity between AChE1 and AChE2 is mainly attributed to decreased binding affinity for the inhibitor.

Acetylcholinesterase (AChE) is a key enzyme of the cholinergic nervous system and has two subtypes, AChE1 and AChE2. Taking the most potent AChE inhibitor, the syn1-TZ2PA6 and its anti-isomer, as representative, comprehensive molecular dynamics (MD) simulations was performed to uncover the selectivity mechanism of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2. This computational insight could guide the design of drugs that selectively inhibit AChE1 or AChE2.Figure optionsDownload high-quality image (177 K)Download as PowerPoint slideHighlights
► We report the selectivity mechanism of the syn1-TZ2PA6 and anti1-TZ2PA6 isomers for AChE1 and AChE2.
► We employed molecular dynamic simulations and binding free energy calculation.
► Calculated data was in good agreement with experimental values.