Abstract
BackgroundThe inhibition of the activity of β-secretase (BACE-1) is a potentially important approach for the treatment of Alzheimer disease. To explore the mechanism of inhibition, we describe the use of 46 X-ray crystallographic BACE-1/inhibitor complexes to derive quantitative structure-activity relationship (QSAR) models. The inhibitors were aligned by superimposing 46 X-ray crystallographic BACE-1/inhibitor complexes, and gCOMBINE software was used to perform COMparative BINding Energy (COMBINE) analysis on these 46 minimized BACE-1/inhibitor complexes. The major advantage of the COMBINE analysis is that it can quantitatively extract key residues involved in binding the ligand and identify the nature of the interactions between the ligand and receptor.ResultsBy considering the contributions of the protein residues to the electrostatic and van der Waals intermolecular interaction energies, two predictive and robust COMBINE models were developed: (i) the 3-PC distance-dependent dielectric constant model (built from a single X-ray crystal structure) with a q2 value of 0.74 and an SDEC value of 0.521; and (ii) the 5-PC sigmoidal electrostatic model (built from the actual complexes present in the Brookhaven Protein Data Bank) with a q2 value of 0.79 and an SDEC value of 0.41.ConclusionsThese QSAR models and the information describing the inhibition provide useful insights into the design of novel inhibitors via the optimization of the interactions between ligands and those key residues of BACE-1.
Highlights
The inhibition of the activity of β-secretase (BACE-1) is a potentially important approach for the treatment of Alzheimer disease
To glean critical information regarding the interactions of the inhibitors with the residues in the active site of BACE-1, we conducted a 3D-quantitative structure-activity relationship (QSAR) study of 46 BACE-1/inhibitor complexes using the COMparative BINding Energy (COMBINE) method
Structural data suggest the average distance between the carboxyl oxygens of the catalytic Asp dyad is 2.5–3.5 Å for all 46 complexes (Figure 1), it indicates that hydrogen bonding between Asp32 and Asp228 is possible in the presence of a substrate
Summary
By considering the contributions of the protein residues to the electrostatic and van der Waals intermolecular interaction energies, two predictive and robust COMBINE models were developed: (i) the 3-PC distance-dependent dielectric constant model (built from a single X-ray crystal structure) with a q2 value of 0.74 and an SDEC value of 0.521; and (ii) the 5-PC sigmoidal electrostatic model (built from the actual complexes present in the Brookhaven Protein Data Bank) with a q2 value of 0.79 and an SDEC value of 0.41
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