title: Virtual target screening: validation using kinase inhibitors.
abstract: Computational methods involving virtual screening could potentially be employed to discover new biomolecular targets for an individual molecule of interest (MOI). However, existing scoring functions may not accurately differentiate proteins to which the MOI binds from a larger set of macromolecules in a protein structural database. An MOI will most likely have varying degrees of predicted binding affinities to many protein targets. However, correctly interpreting a docking score as a hit for the MOI docked to any individual protein can be problematic. In our method, which we term "Virtual Target Screening (VTS)", a set of small drug-like molecules are docked against each structure in the protein library to produce benchmark statistics. This calibration provides a reference for each protein so that hits can be identified for an MOI. VTS can then be used as tool for: drug repositioning (repurposing), specificity and toxicity testing, identifying potential metabolites, probing protein structures for allosteric sites, and testing focused libraries (collection of MOIs with similar chemotypes) for selectivity. To validate our VTS method, twenty kinase inhibitors were docked to a collection of calibrated protein structures. Here, we report our results where VTS predicted protein kinases as hits in preference to other proteins in our database. Concurrently, a graphical interface for VTS was developed.
authors: Department of Chemistry, University of South Florida, Tampa, Florida 33620, USA.
authors: Daniel N
authors: DN
authors: Santiago
authors: Yuri
authors: Y
authors: Pevzner
authors: Ashley A
authors: AA
authors: Durand
authors: MinhPhuong
authors: M
authors: Tran
authors: Rachel R
authors: RR
authors: Scheerer
authors: Kenyon
authors: K
authors: Daniel
authors: Shen-Shu
authors: SS
authors: Sung
authors: H Lee
authors: HL
authors: Woodcock
authors: Wayne C
authors: WC
authors: Guida
authors: Wesley H
authors: WH
authors: Brooks
mesh_terms: D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D030562:Databases, Protein; D017277:Drug Approval; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014584:User-Computer Interface
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases; D051357:Cyclin-Dependent Kinase 2