In silico Screening of Pyridoxine Carbamates for Anti-Alzheimer's Activities.

Background: Alzheimer's disease (AD), an irreversible complex neurodegenerative disorder, is the most common type of dementia, with progressive loss of cholinergic neurons. Based on the multi-factorial etiology of Alzheimer's disease, novel ligands strategy appears as an up-coming approach for the development of newer molecules against AD. This study is envisaged to investigate anti-Alzheimer's potential of 10 synthesized compounds. The screening of compounds (1-10) was carried out using in silico techniques.

Methods: For in silico screening of physicochemical properties of compounds, Molinspiration property engine v.2018.03, Swiss ADME online web-server and pkCSM ADME were used. For pharmacodynamic prediction, PASS software was used, while the toxicity profile of compounds was analyzed through ProTox-II online software. Simultaneously, molecular docking analysis was performed on mouse AChE enzyme (PDB ID:2JGE, obtained from RSCB PDB) using Auto Dock Tools 1.5.6.

Results: Based on in silico studies, compound 9 and 10 have been found to have better druglikeness, LD50 value, better anti-Alzheimer's, and nootropic activities. However, these compounds had poor blood-brain barrier (BBB) permeability. Compounds 4 and 9 were predicted with a better docking score for the AChE enzyme.

Conclusion: The outcome of in silico studies has suggested, out of various substitutions at different positions of pyridoxine-carbamate, compound 9 has shown promising drug-likeness, with better safety and efficacy profile for anti-Alzheimer's activity. However, BBB permeability appears as one of the major limitations of all these compounds. Further studies are required to confirm its biological activities.