title: Structure-guided selection of specificity determining positions in the human Kinome.
abstract: The human kinome contains many important drug targets. It is well-known that inhibitors of protein kinases bind with very different selectivity profiles. This is also the case for inhibitors of many other protein families. The increased availability of protein 3D structures has provided much information on the structural variation within a given protein family. However, the relationship between structural variations and binding specificity is complex and incompletely understood. We have developed a structural bioinformatics approach which provides an analysis of key determinants of binding selectivity as a tool to enhance the rational design of drugs with a specific selectivity profile.
  
  
  
  We propose a greedy algorithm that computes a subset of residue positions in a multiple sequence alignment such that structural and chemical variation in those positions helps explain known binding affinities. By providing this information, the main purpose of the algorithm is to provide experimentalists with possible insights into how the selectivity profile of certain inhibitors is achieved, which is useful for lead optimization. In addition, the algorithm can also be used to predict binding affinities for structures whose affinity for a given inhibitor is unknown. The algorithm's performance is demonstrated using an extensive dataset for the human kinome.
  
  
  
  We show that the binding affinity of 38 different kinase inhibitors can be explained with consistently high precision and accuracy using the variation of at most six residue positions in the kinome binding site. We show for several inhibitors that we are able to identify residues that are known to be functionally important.
authors.affiliation: Department of Computer Science, Rice University, PO Box 1892, Houston, 77251, TX, USA. mmoll@rice.edu.
authors.forename: Mark
authors.initials: M
authors.lastname: Moll
authors.affiliation: University of Buckingham, Hunter St, Buckingham, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Finn
authors.affiliation: Department of Computer Science, Rice University, PO Box 1892, Houston, 77251, TX, USA.
authors.forename: Lydia E
authors.initials: LE
authors.lastname: Kavraki
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D015894:Genome, Human; D006801:Humans; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment / Q000379:methods*; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases
keywords: Binding affinity; Protein kinases; Specificity determining positions