Abstract
Background: Aggregation of Amyloid beta (A beta) peptide is a crucial feature of Alzheimer disease (AD) pathogenesis. In fact, A beta peptides are misfolded and aggregated to frame Amyloid fibrils, which is considered as one of the major contributing events in the onset of AD. All these observations have prompted the researchers to design therapeutic molecules with robust anti-A beta aggregation potential. Interestingly, in the last few decades, drug repurposing has turned into a fruitful and savvy approach for the treatment of several diseases. Bexarotene is an anticancer drug that has been under consideration for its ability to suppress A beta-peptide aggregation. However, the exact mechanistic aspect of suppression of A beta-peptide accumulation has not yet been completely revealed.
Methods: In the present study, we have attempted to decipher the mechanistic aspects of the anti-aggregation potential of bexarotene by using the computational biology approach.
Results: We have observed the effect of 'A beta-bexarotene' interaction on the aggregation ability of the A beta-peptide and decoded the involvement of receptor for advanced glycation end products (RAGE) and beta-secretase (BACE-1). A deep structural analysis of A beta upon binding with bexarotene revealed critical binding sites and structural twists involved in A beta aggregation. it is evident from the present that bexarotene could significantly restrain the process of primary nucleation of A beta. In addition, bexarotene showed a strong interaction with RAGE and BACE-1, suggesting them as plausible targets for the neuro-therapeutic action of bexarotene.
Conclusion: Hence, we could safely suggest that bexarotene is a potent drug candidate that could reduce A beta-peptide aggregation by applying different mechanistic pathways. These results might boost the portfolio of pharmaceutical companies looking for the development of new chemical entities against AD.