Application of Free-Wilson selectivity analysis for combinatorial library design.
In this chapter we present an application of in silico quantitative structure-activity relationship (QSAR) models to establish a new ligand-based computational approach for generating virtual libraries. The Free-Wilson methodology was applied to extract rules from two data sets containing compounds which were screened against either kinase or PDE gene family panels. The rules were used to make predictions for all compounds enumerated from their respective virtual libraries. We also demonstrate the construction of R-group selectivity profiles by deriving activity contributions against each protein target using the QSAR models. Such selectivity profiles were used together with protein structural information from X-ray data to provide a better understanding of the subtle selectivity relationships between kinase and PDE family members.
Sciabola
Simone
S
Pfizer Research Technology Center, Cambridge, MA, USA. simone.sciabola@pfizer.com
Stanton
Robert V
RV
Johnson
Theresa L
TL
Xi
Hualin
H
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D019295:Computational Biology / Q000379:methods*; D018360:Crystallography, X-Ray; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D016014:Linear Models; D008958:Models, Molecular; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D012044:Regression Analysis; D015203:Reproducibility of Results; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013379:Substrate Specificity; D014584:User-Computer Interface
D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases; D010727:Phosphoric Diester Hydrolases