title: Prediction of specificity-determining residues for small-molecule kinase inhibitors.
abstract: BACKGROUND
  Designing small-molecule kinase inhibitors with desirable selectivity profiles is a major challenge in drug discovery. A high-throughput screen for inhibitors of a given kinase will typically yield many compounds that inhibit more than one kinase. A series of chemical modifications are usually required before a compound exhibits an acceptable selectivity profile. Rationalizing the selectivity profile for a small-molecule inhibitor in terms of the specificity-determining kinase residues for that molecule can be an important step toward the goal of developing selective kinase inhibitors.
  
  
  RESULTS
  Here we describe S-Filter, a method that combines sequence and structural information to predict specificity-determining residues for a small molecule and its kinase selectivity profile. Analysis was performed on seven selective kinase inhibitors where a structural basis for selectivity is known. S-Filter correctly predicts specificity determinants that were described by independent groups. S-Filter also predicts a number of novel specificity determinants that can often be justified by further structural comparison.
  
  
  CONCLUSIONS
  S-Filter is a valuable tool for analyzing kinase selectivity profiles. The method identifies potential specificity determinants that are not readily apparent, and provokes further investigation at the structural level.
authors.affiliation: Pfizer Research Technology Center, 620 Memorial Drive, Cambridge, MA 02139, USA. daniel.caffrey@gmail.com
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Caffrey
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Lunney
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Moshinsky
mesh_terms: D001665:Binding Sites / Q000235:genetics; D030541:Databases, Genetic; D023281:Genomics / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism; D040901:Proteomics / Q000379:methods*; D020539:Sequence Analysis, Protein / Q000379:methods*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases