Molecular recognition of acetylcholinesterase and its subnanomolar reversible inhibitor: a molecular simulations study

Abstract

Recently, we designed and synthesized a subnanomolar, reversible, dual-binding site acetylcholinesterase (AChE) inhibitor which consists of the tacrine and aroylacrylic acid phenylamide moieties, mutually linked by eight methylene units. To further investigate the process of the molecular recognition between the AChE and its inhibitor, we performed six unconstrained molecular dynamics (MD) simulations, where the compound in three possible protonation states was placed inside binding sites of two available AChE crystal structures. In all six MD trajectories, the ligand generally occupied similar space inside the AChE active site, but the pattern of the interactions between the ligand functional groups and the amino acid residues was significantly different and highly dependent upon the crystal structure used to generate initial systems for simulation. The greatest differences were observed between the trajectories obtained with different AChE crystal structures used as starting target conformations. In some trajectories, several unusual positions and dynamic behavior of the tacrine moiety were observed. Therefore, this study provides important structure-based data useful in further optimization of the reversible, dual binding AChE inhibitors, and also emphasizes the importance of the starting crystal structure used for dynamics as well as the protonation state of the reversible inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular dynamic simulations
• protonation microstates
• ligand-protein recognition
• acetylcholinesterase
• reversible inhibition
• tacrine

Acknowledgments

The authors are grateful to prof. Gerhard Wolber for providing access to dynophore calculations using computer facilities at the FreieUniversität Berlin, Germany.

Disclosure statement

The authors declare no conflict of interest. MZ is founder and director of Nanopuzzle Medicines Design Ltd, that will derive no financial gain from this work.

Funding

AP was supported by the Ministry of Higher Education, Science and Technology of the Republic of Slovenia through Research Program Grant P1-0012. MVT was supported by the Ministry of Defense of the Republic of Serbia and by the Ministry of Education, Science and Technological Development of the Republic of Serbia and I.C. acknowledges financial support from Ministry of Education, Science and Technological development of Serbia, Contract number: 451-03-68/2020-14/200288.

Scheme 1. The schematic view of the interactions between the ligand and AChE amino acid residues obtained by the dynophore analysis.