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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. [ABSTRACT FROM AUTHOR]

In the present work, a combined approach based on conceptual-DFT formalism and molecular docking simulations were performed to investigate the chemical reactivity of six Benzodiazepine analogs. Chemical reactivity descriptors derived from the conceptual DFT were determined and discussed to explain the global and local reactivity of the six studied analogs. Also, long-range interactions were studied using the quantitative analyses of molecular electrostatic potential (MEP) on van der Waals surface to identify the nucleophilic and electrophilic sites. Moreover, a statistical analysis was performed to assess the robustness of atomic charges to the basis set. The results revealed that Hirshfeld population analysis (HPA) was the most efficient for this purpose. Molecular docking simulations were performed to predict the binding affinities of the issued molecules and estimate the binding poses into four binding sites, three of them were recently discovered, located in GABAA receptor. [ABSTRACT FROM AUTHOR]