Investigation of spirooxindole-pyrrolidine derivatives as acetylcholinesterase inhibitors using molecular docking/dynamics simulations, bioisosteric replacement, MEP, and ADME/Tox properties

• Published in: Biológia Vol. 78; no. 12; pp. 3691 - 3711
• Main Authors: Kherachi, Rania, Daoud, Ismail, Melkemi, Nadjib, Kenouche, Samir, Mettai, Merzaka, Mesli, Fouzia
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.12.2023; Springer Nature B.V
• Subjects: Acetylcholinesterase; Affinity; Alzheimer's disease; Analogs; Antibacterial activity; Binding sites; Bioavailability; Biomedical and Life Sciences; Cell Biology; Chemical bonds; Cholinesterase inhibitors; Clinical trials; Donepezil; Drug development; Hydrogen bonding; Hydrogen bonds; Inhibitors; Life Sciences; Microbiology; Molecular docking; Molecular modelling; Molecular structure; Neurodegenerative diseases; Original Article; Physicochemical properties; Plant Sciences; Pyrrolidine; Simulation; Simulation analysis; Tacrine; Zoology; MEP analysis; AChE; Molecular docking/Dynamics; Bioisosteric replacement; Spirooxindole-pyrrolidine derivatives; ADME-T
• ISSN: 1336-9563; 0006-3088; 1336-9563
• DOI: 10.1007/s11756-023-01528-x

Acetylcholinesterase is used as a key target in the treatment of Alzheimer's disease. Recently, a series of new spirooxindolepyrrolidine derivatives were synthesized and preliminarily shown to have antibacterial activity and potential acetylcholinesterase inhibitors. For this reason, the current investigation examine 35 compounds in this series as acetylcholinesterase inhibitors and compare them to clinical trials using different molecular modeling methods, including molecular docking/dynamics simulations, MEP analysis, bioisosteric replacement, and ADME-T prediction. Molecular docking studies describe the hierarchical structure of the interaction between spirooxindolepyrrolidine derivatives and the AChE receptor, showing that compounds L27 and L28 have a high affinity (Score energies: -5.858 and -5.961 kcal/mol, respectively) with the binding site of the studied target. These results were confirmed by slighter conformational changes during the MD simulation analysis of the AChE-L27 and AChE-L28 complexes compared to tacrine and donepezil. Furthermore, the bioisosteric substitution approach was successfully applied; proposing two new analogs of each compound showing low energy scores ​​ and an important number of hydrogen bonds. In addition, ADME-Tox prediction and the different physicochemical properties of the best compounds (L27 and L28) were also used to evaluate their relevance as drug candidates they're and validate their favorable oral bioavailability. Thus, an in silico study showed that compounds L27, L28, and their analogs exhibit strong binding affinity towards the active site residues of the AChE target, suggesting that they may be potent inhibitors of Alzheimer's disease. Graphical abstract