In Silico Investigation of Amidine-Based BACE-1 Inhibitors Against Alzheimer’s Disease: SAR, Pharmacokinetics, Molecular Docking and Dynamic Simulations

<b>Background/Objective:</b> Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β plaques, derived from the amyloid precursor protein through sequential cleavage by β-secretase 1 (BACE-1) and γ-secretase. BACE-1 is therefore a key drug target for designing of selective inhibitors to avoid off-target effects associated with BACE-2 inhibition. The objective of this study was to design novel BACE-1 inhibitors using a structure-based drug design approach. <b>Methods:</b> A focused compound library was designed based on the SAR of N-(4-fluorophenyl)formamide derivatives. <i>In silico</i> ADME predictions were performed to assess pharmacokinetic suitability. Compounds showing favorable ADME profiles were subjected to molecular docking against the BACE-1 enzyme. The top-scoring hit, compound <b>9.7</b> (-5.48 (kcal/mol), was further evaluated using a 200 ns MD simulation to assess the stability of its binding interactions with BACE-1. <b>Results:</b> Designed compounds indicated acceptable physicochemical and ADME characteristics. Molecular docking identified compound <b>9.7</b> as exhibiting favorable binding interactions with binding pocket residues of BACE-1. The 200 ns MD simulation further confirmed the stability of the docked complex. MD simulations confirmed that 9.7 forms stable interactions with the catalytic residue ASP32 and key hydrophobic residues TRP115 and PHE108 of BACE-1. These important interactions are absent in the reference compound verubecestat. <b>Conclusions:</b> The multi-step computational analysis suggests that compound <b>9.7</b> is a promising and selective BACE-1 inhibitor. Its favorable ADME profile, favorable docking interactions, and stable MD simulation behavior highlight its potential as a hit compound for further optimization in the development of anti-Alzheimer's agents.