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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm049133b

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.