LAUSR

Alzheimer's disease (AD) is clinically characterized by the aggregation of neurotoxic amyloid‐β (Aβ) peptides in the brain. γ‐Secretase catalyzes the reaction of Aβ formation. Inhibition of γ‐secretase activating protein (GSAP) reduces Aβ production without disrupting other molecular functions and serves as a promising therapeutic target for lowering Aβ and curing AD. Till date, no proven drug is available for curing AD because of the nonexistence of crystal/NMR structure of GSAP. Thus in the present study, for the first time, we adopted in silico method to predict the 3D structure of GSAP via comparative modeling and studied the architecture and function of GSAP through simulation studies. Docking studies with 4153 phytochemicals revealed that GSAP having a better binding affinity with macaflavanone C, (E)‐1‐[2,4‐dihydroxy‐3‐(3‐methylbut‐2‐enyl)phenyl]‐3‐(2,2‐dimethyl‐8‐hydroxy‐2H‐benzopyran‐6‐yl)prop‐2‐en‐1‐one, and monachosorin B as compared with the standard drug, imatinib. Further, the molecular dynamics analysis suggested that only two phytochemicals, namely, macaflavanone C and (E)‐1‐[2,4‐dihydroxy‐3‐(3‐methylbut‐2‐enyl)phenyl]‐3‐(2,2‐dimethyl‐8‐hydroxy‐2H‐benzopyran‐6‐yl)prop‐2‐en‐1‐one) significantly disrupt the original property of GSAP and also cleared the absorption, distribution, metabolism, and excretion test. These natural compounds may be utilized in future for curing AD after further investigations.