Search and validation of a versatile amyloid inhibitor

Amyloids are highly ordered, insoluble, peptide or protein aggregates involved in various neurodegenerative diseases. TDP - 43 is a major amyloid forming protein associated with Amyotrophic lateral sc lerosis (ALS) and some other neurodegenerative diseases. There is no cure for ALS till date. In our lab, a small molecule which is an acridine derivative (AIM4) has been shown to have anti TDP - 43 aggregation property, in ALS disease model. In this study we have tried to find the binding mechanism of AIM4 to TDP - 43 through molecular docking study. AIM4 binds to the amyloidogenic core region of TDP - 43 with better binding affinity compared to other compounds tested, in accordance with in - vitro data. Further mo lecular dynamics simulation revealed the stability of the complex formed by TDP - 43 and AIM4. Next, to probe the versatility of AIM4, docking and simulation study were carried out with Aβ40 and Aβ42 peptides. AIM4 has been shown to have better binding affinity with Aβ40 and Aβ42 compared to known Aβ inhibitors like curcumin and AO - 11. Simulation st udies have confirmed the stability of the complexes of Aβ with AIM4