Organoselenium Compounds as Acetylcholinesterase Inhibitors: Evidence and Mechanism of Mixed Inhibition

• DOI: 10.1021/acs.jpcb.0c08111
• Publication Date: 2021-02-06T13:25:52Z
• Authors: Amit Kumawat; Shabnam Raheem; Fasil Ali; Tanveer Ali Dar; Suman Chakrabarty; Masood Ahmad Rizvi
• Keywords: fluorescence assays; Chemical Sciences not elsewhere classified; Information Systems not elsewhere classified; Biophysics; Molecular Dynamics Simulation; AChE inhibitors; Acetylcholinesterase Inhibitors; Biochemistry; DPDSe molecule; binding modes; 03 medical and health sciences; Organoselenium Compounds; Mixed Inhibition Acetylcholinesterase; Molecular Biology; diphenyl diselenide; PAS-binding inhibitors; Cancer; Pharmacology; non-specific interactions; neuroprotective effects; MD simulations; 0303 health sciences; Binding Sites; AChE activity; entry point; allosteric hotspots; inhibition; 3. Good health; Molecular Docking Simulation; substrate entry point; Acetylcholinesterase; Cholinesterase Inhibitors; ebselen; Physical Sciences not elsewhere classified; Neuroscience; Biotechnology; Biological Sciences not elsewhere classified

Acetylcholinesterase (AChE) inhibitors are actively used for the effective treatment of Alzheimer's disease. In recent years, the neuroprotective effects of organoselenium compounds such as ebselen and diselenides on the AChE activity have been investigated as potential therapeutic agents. In this work, we have carried out systematic kinetic and intrinsic fluorescence assays in combination with docking and molecular dynamics (MD) simulations to elucidate the molecular mechanism of the mixed inhibition of AChE by ebselen and diphenyl diselenide (DPDSe) molecules. Our MD simulations demonstrate significant heterogeneity in the binding modes and allosteric hotspots for DPDSe on AChE due to non-specific interactions. We have further identified that both ebselen and DPDSe can strongly bind around the peripheral anionic site (PAS), leading to non-competitive inhibition similar to other PAS-binding inhibitors. We also illustrate the entry of the DPDSe molecule into the gorge through a "side door", which offers an alternate entry point for AChE inhibitors as compared to the usual substrate entry point of the gorge. Together with results from experiments, these simulations provide mechanistic insights into the mixed type of inhibition for AChE using DPDSe as a promising inhibitor for AChE.