Exploring Pyranophenothiazines for Anti-Alzheimer’s Activity: Insights from Molecular Modeling Analysis

Introduction: Alzheimer’s disease (AD) is a neurodegenerative disorder. Obstructing AChE is a remedial strategy to increase ACh levels in the brain and potentially upgrade cognitive function. In the realm of anti-Alzheimer's agents, pyranophenothiazine has been a noteworthy compound that exhibits significant inhibitory activity toward relevant receptors. Objective: Novel analogs of pyranophenothiazine were intricately crafted, and their inhibitory potential against AChE enzyme (4EY7) and BuChE enzyme (4AQD) was thoroughly investigated through molecular modeling studies. Methods: In silico ADMET predictions were carried out by using the QikProp module. Docking studies were conducted by using the Glide module for two targets: AChE enzyme (PDB id: 4EY7) and BuChE enzyme(PDB id: 4AQD). Binding free energies were calculated by means of the Prime MM-GBSA module, and molecular dynamics (MD) simulation was performed by using the Desmond module. method: Docking studies were conducted by using Glide module; binding free energies were calculated by means of Prime MM-GBSA module and Molecular dynamics (MD) simulation was performed by using Desmond module. Results and Discussion: These results of ADMET predictions indicated that the compounds possess drug-likeness properties, making them suitable candidates for further development and also having the ability to cross the BBB. The docking studies revealed the interaction between the designed ligands and cholinesterases. The results indicate that the ligands exhibit significant binding affinities, which was confirmed by MM-GBSA analysis and MD simulation study. Conclusion: Conclusively, the study findings suggest that derivatives of pyranophenothiazine hold potential as inhibitors of AChE targeting AD.