Identification of new BACE1 inhibitors using Pharmacophore and Molecular dynamics simulations approach

Inhibition of β-Secretase (BACE1) is crucial for the treatment of Alzheimer's disease (AD). Availability of BACE1 crystal structures in both apo and complexed forms enables to find structure-based BACE1 inhibitors for controlling AD. There are two catalytic aspartates (ASP32 and ASP228) presents in the active domain of BACE1. In order to understand the binding mechanism and structure-activity relationship of amidine-containing BACE1 inhibitors, molecular docking, and pharmacophore and 3D-QSAR studies have been carried out with 34 amidine derivatives to develop a pharmacophore model. Pharmacophore-based virtual screening (PBVS) has been performed against BACE1 (PDB ID: 2FDP), using three chemical databases (CoCoCo, Enamine, Zinc), which yielded 6000 hit compounds. These compounds were further analyzed using structure-based docking in hierarchical filtering approaches of Glide such as HTVS, SP, and XP precision modes. The docking results show that binding orientations of the inhibitors at Asp dyad active site amino acid residues of β-Secretase. Results from glide XP docking and induced fit docking showed that four leads (Lead1, Lead3, Lead4 and Lead5) have good interactions with the target protein in comparison with cocrystal (amino-ethylene BACE1 inhibitor). Further, molecular dynamics (MD) simulation for these leads bound with BACE1 shows conformational stability and difference in dynamical flap behaviors of the active site with cocrystal inhibitor. Binding free energetic using MM-GB/SA approaches suggest lead 1 and lead 3 has comparably favorable binding to cocrystal inhibitor. Thus, the present study emphasizes these leads for an effective drug to treat Alzheimer disease.