Insight into the anti-amyloidogenic activity of polyphenols and its application in virtual screening of phytochemical database

摘要

Alzheimer's Disease (AD) is the most frequent form of neurodegenerative disorder pathologically characterized by the presence of aggregates of A(3 in the region of the brain involved in memory and cognition. Polyphenols commonly found in several daily consumed food items and beverages have been demonstrated to inhibit A(3 aggregation using various biophysical or cell culture-based techniques. Here, insight into the anti-amyloidogenic activity of polyphenols has been explored using 2-D QSAR methodology implemented in CODESSA packages. Interestingly, hydrophobic interactions emerge as a significant descriptor for the recognition of amyloid fibril by polyphenols. Thus, it may be interpreted that highly potent polyphenols capably bind within the hydrophobic core region of the amyloid fibril and, thereby, destabilize the fibril by interrupting the hydrophobic interactions present within the fibril. Highly branched substituents and sub-stituents with high degree of conformational flexibility on the polyphenolic structural scaffold enhance the fibril-destabilizing activity of compounds. In addition, specific electrostatic interaction between amyloid fibril and poly-phenol plays a crucial role for the recognition of the fibril by polyphenols. The "application domain" of the derived QSAR model also has been defined, and the derived model has been used to screen a small in-house developed phy-tochemicals database comprising 200 compounds. 59 phytochemicals have been predicted as highly active anti-amyloidogenic phytochemicals. The modeling strategy is an efficient way to reduce the chemical search space and can selectively mine novel lead anti-amyloidogenic molecule from large chemical databases.