High-throughput virtual screening of proteins using GRID molecular interaction fields.
A new computational algorithm for protein binding sites characterization and comparison has been developed, which uses a common reference framework of the projected ligand-space four-point pharmacophore fingerprints, includes cavity shape, and can be used with diverse proteins as no structural alignment is required. Protein binding sites are first described using GRID molecular interaction fields (GRID-MIFs), and the FLAP (fingerprints for ligands and proteins) method is then used to encode and compare this information. The discriminating power of the algorithm and its applicability for large-scale protein analysis was validated by analyzing various scenarios: clustering of kinase protein families in a relevant manner, predicting ligand activity across related targets, and protein-protein virtual screening. In all cases the results showed the effectiveness of the GRID-FLAP method and its potential use in applications such as identifying selectivity targets and tools/hits for new targets via the identification of other proteins with pharmacophorically similar binding sites.
Sciabola
Simone
S
Pfizer Research Technology Center, Cambridge, Massachusetts 02139, Pfizer Global Research and Development, Ramsgate Road, Kent CT139NJ, Sandwich, United Kingdom. simone.sciabola@pfizer.com
Stanton
Robert V
RV
Mills
James E
JE
Flocco
Maria M
MM
Baroni
Massimo
M
Cruciani
Gabriele
G
Perruccio
Francesca
F
Mason
Jonathan S
JS
D001665:Binding Sites; D002826:Chorismate Mutase / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004926:Escherichia coli / Q000201:enzymology; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010770:Phosphotransferases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D019311:Staurosporine / Q000378:metabolism / Q000494:pharmacology; D014584:User-Computer Interface
D008024:Ligands; D011506:Proteins; D010770:Phosphotransferases; D002826:Chorismate Mutase; D019311:Staurosporine