IDENTIFICATION OF SERPENTINE AS PROMISING BACE 1 INHIBITORS: A COMPUTATIONAL APPROACH TO EXPLORE NOVEL STRATEGIES FOR ALZHEIMER’S THERAPY

Abstract

Aim: This study aims to identify and characterize serpentine as potential BACE1 inhibitors by in-silico approach as an alternate therapeutic approach towards Alzheimer’s. It is a neurodegenerative condition involving multiple factors and currently there is no cure. It is primarily driven by abnormal production and buildup of amyloid β peptides that are formed by sequential processing of APP mediated by the action of BACE1 and γ-secretase. While BACE 1 has been identified as potential therapeutic target molecule and many drug candidates have been tested in clinical trials but they show limited cognitive benefits and many cases produced off-target side effects. Due to this, the attention is shifted toward naturally occurring molecules that may offer safer and more effective inhibition of BACE 1. In this study, serpentine, an indole alkaloid found in Catharanthus roseus and its stereoisomers were evaluated using an integrated insilico screening approach. A PubChem similarity search with 90 percent Tanimoto similarity threshold produced 116 serpentine related compounds, which were further shortlisted through ADME based filtering to select drug like candidates. Molecular docking was performed that utilized Lamarckian genetic algorithm with Verubecestat as the reference molecule. Eleven shortlisted compounds show stronger binding affinities than the reference inhibitor, with serpentine (PubChem CID 73073) showing the highest affinity. Analysis of protein ligand interactions revealed the involvement of BACE 1 residues, including Tyr71, Gln73 and Thr232. Conclusively, this novel findings indicate that serpentine and its stereoisomers may serve as promising lead molecules for designing future BACE1-focused treatments for Alzheimer’s disease and is strongly advised for in vivo analysis.

Result: During the course of our study, initially 116 related compounds were produced and further shortlisted based on ADME analysis left us with 14 compounds which were all BBB permeable. Docking analysis of these compounds identified eleven with binding affinities higher than the reference, Verubecestat (-7.946kcal/mol), with the highest affinity of -9.329 in kcal/mol. Conclusion: Among the eleven identified compounds, Compound 1 was the most effective treatment for Alzheimer’s disease, with the highest binding affinity and being BBB permeable. We suggest validating these findings through in vivo experiments