Fig 1.
Structural characterization and active site analysis of Beta Secretase 1 (BACE1) for structure-based drug design. A) 3D structure of BACE1 (PDB ID 2QP8) with active site residues in chain A and B. B) Active site of BACE1; white spheres show hydrophobic residues whereas red spheres show hydrophilic residues, C) Zoomed-in view of the active site residues of BACE1. D) Superimposition of the BACE1 crystal structure (blue) and the docked protein (pink) showing the alignment of native and docked ligands. E) Zoomed-in view of the native ligand SCH734723 (orange) superimposed with its docked pose (cyan) within the active site surface (yellow).
Table 1.
Molecular docking scores, estimated inhibition constants (Ki), and detailed binding interactions of the lead compounds within the BACE1 active site, observed in Molecular Operating Environment (MOE).
Fig 2.
2D and 3D (A-C) interaction representation of standard (MK-8931) with BACE1.
Fig 3.
Ligand-protein interactions of four lead compounds (1-4) with with BACE1.
Panel A-D shows 3D and 2D interactions of the corresponding ligands with the active site of BACE1. Melberrofuran G (compound 1), Tellimagrandin I (compound 2), Geraniin (compound 3) and 2-[(9Z,12Z)-heptadeca-9,12-dienyl]-6-hydroxybenzoic acid (compound 4).
Fig 4.
Ligand-protein interactions of four lead compounds (5-8) with BACE1.
Panels A-D shows 3D and 2D interactions of the corresponding ligands with the active site of BACE1. 1, 2, 3, 6-Tetra-O-galloyl-beta-D-glucose (compound 5), Sargachromenol (compound 6), Dieckol (compound 7) and Chrysophanol tetraglucoside (compound 8).
Fig 5.
Ligand-protein interactions of two lead compounds (9-10) with BACE1.
Panels A-B shows 3D and 2D interactions of the corresponding ligands with the active site of BACE1. Neferine (compound 9) and 2-O-coumaryl-S-aloesinol (compound 10).
Fig 6.
Binding interactions analysis of palmatine and berberine complexes with BACE1. A) Palmatine and berberine in complex with BACE1. B) 3D and 2D binding interaction of palmatine with BACE1. Palmatine (shown in yellow) molecular surface shown in red color. C) 3D and 2D binding interaction of berberine with BACE1. Berberine (shown in purple) hydrophobic interactions shown in grey.
Fig 7.
BACE1 with the lead compounds superimposed onto the respective binding sites.
Eight and four ligands were bound to the active sites at chain A and B, respectively.
Fig 8.
MD simulation trajectories are statistically analyzed.
(A) Protein backbone RMSD (B) Ligand RMSD (C) RMSF and (D) ROG are the four output values. Binding conformation modifications of Berberine (Top) shown in different color sticks at the binding pocket of BACE1 protein (shown in grey color). Palmatine binding conformation changes (Bottom) shown as different coloured sticks in the BACE1 protein’s binding pocket (shown in grey color).
Table 2.
Physicochemical parameters and drug-likeness of top compounds.
Fig 9.
Pharmacokinetic analysis of top 50 compounds indicates palmatine (45) and berberine (49) within the BBB permeability range (Egg yolk), while others are outside this range (Egg white).
Table 3.
Pharmacokinetics parameters of top 50 compounds.
Table 4.
Toxicity prediction and probability of top 50 compounds.
Fig 10.
Pharmacophoric features of palmatine (A), berberine (B) and MK-8931 (C).
Acc (hydrogen acceptor), Don (hydrogen donor), Hyd (hydrophobic), Aro (aromatic), PiN (Pi Network), and Cat (cationic interaction).