DFT analysis of gamma-secretase interactions with potential inhibitors: therapeutic for Alzheimer's disease.
Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to cognitive decline. The enzyme γ-secretase (γS) plays a central role in Aβ production and is therefore an important therapeutic target. In this study, interaction energies were evaluated using the Molecular Fragmentation with Conjugated Caps (MFCC) method combined with Density Functional Theory (DFT) calculations to investigate the interactions between γS and the inhibitors Semagacestat (SEM) and Avagacestat (AVA). The SEM-γS complex exhibited a more favorable total interaction energy, primarily driven by interactions with residues such as Ala431, Lys380, and Leu425. In contrast, the AVA-γS complex showed prominent interactions involving key residues, including Leu381, Leu425, and Leu432, which participate in substrate recognition and stabilization within the enzymes binding pocket. Overall, both ligands highlight the combined importance of hydrophobic and hydrophilic interactions in stabilizing the complexes. This study provides molecular-level insights into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.