Virtual Screening for β-Secretase (BACE1) Inhibitors Reveals the Importance of Protonation States at Asp32 and Asp228

A comparative virtual screen for β-secretase (BACE1) inhibitors using different docking methods (FlexX and FlexX-Pharm), scoring functions (Dock, Gold, Chem, PMF, FlexX), protonation states (default and calculated), and protein conformations (apo and ligand bound) has been performed. Apo and ligand...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2005-06, Vol.48 (11), p.3749-3755
Main Authors: POLGAR, Timea, KESERÜ, György M
Format: Article
Language:English
Subjects:
Amyloid Precursor Protein Secretases
Aspartic Acid - chemistry
Binding Sites
Biological and medical sciences
Crystallography, X-Ray
Endopeptidases - chemistry
Ligands
Medical sciences
Models, Molecular
Molecular Structure
Neuropharmacology
Pharmacology. Drug treatments
Protease Inhibitors - chemistry
Protein Binding
Protein Conformation
Protons
Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease)
Psychology. Psychoanalysis. Psychiatry
Psychopharmacology
Quantitative Structure-Activity Relationship
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Summary:A comparative virtual screen for β-secretase (BACE1) inhibitors using different docking methods (FlexX and FlexX-Pharm), scoring functions (Dock, Gold, Chem, PMF, FlexX), protonation states (default and calculated), and protein conformations (apo and ligand bound) has been performed. Apo and ligand bound conformations of BACE1 were both found to be suitable for virtual screening. Assigning calculated protonation states to catalytic Asp32 and Asp228 residues resulted in significant improvement of enrichment factors as calculated at 1% of the ranked database. Using 1FKN we obtained no enrichment by FlexX/D-Score that was improved to 36 when considering calculated protonation states. We also show that combining calculated protonation states with pharmacophore constraints using FlexX-Pharm/D-Score improved enrichment further to 41. Enrichments reported in this study suggest our screening protocol will be effective in the virtual screening of large compound libraries for BACE1 inhibitors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm049133b