title: Assessing protein kinase target similarity: Comparing sequence, structure, and cheminformatics approaches.
abstract: In just over two decades, structure based protein kinase inhibitor discovery has grown from trial and error approaches, using individual target structures, to structure and data driven approaches that may aim to optimize inhibition properties across several targets. This is increasingly enabled by the growing availability of potent compounds and kinome-wide binding data. Assessing the prospects for adapting known compounds to new therapeutic uses is thus a key priority for current drug discovery efforts. Tools that can successfully link the diverse information regarding target sequence, structure, and ligand binding properties now accompany a transformation of protein kinase inhibitor research, away from single, block-buster drug models, and toward "personalized medicine" with niche applications and highly specialized research groups. Major hurdles for the transformation to data driven drug discovery include mismatches in data types, and disparities of methods and molecules used; at the core remains the problem that ligand binding energies cannot be predicted precisely from individual structures. However, there is a growing body of experimental data for increasingly successful focussing of efforts: focussed chemical libraries, drug repurposing, polypharmacological design, to name a few. Protein kinase target similarity is easily quantified by sequence, and its relevance to ligand design includes broad classification by key binding sites, evaluation of resistance mutations, and the use of surrogate proteins. Although structural evaluation offers more information, the flexibility of protein kinases, and differences between the crystal and physiological environments may make the use of crystal structures misleading when structures are considered individually. Cheminformatics may enable the "calibration" of sequence and crystal structure information, with statistical methods able to identify key correlates to activity but also here, "the devil is in the details." Examples from specific repurposing and polypharmacology applications illustrate these points. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Osman A
authors.initials: OA
authors.lastname: Gani
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Balmukund
authors.initials: B
authors.lastname: Thakkar
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Dilip
authors.initials: D
authors.lastname: Narayanan
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Kazi A
authors.initials: KA
authors.lastname: Alam
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Peter
authors.initials: P
authors.lastname: Kyomuhendo
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Ulli
authors.initials: U
authors.lastname: Rothweiler
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors.forename: Veronica
authors.initials: V
authors.lastname: Tello-Franco
authors.affiliation: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway. Electronic address: Richard.Engh@uit.no.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Engh
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001665:Binding Sites; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D011494:Protein Kinases / Q000737:chemistry / Q000235:genetics*; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry* / Q000235:genetics; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D047428:Protein Kinase Inhibitors; D054852:Small Molecule Libraries; D011494:Protein Kinases; D016315:Proto-Oncogene Proteins c-abl
keywords: ABL; Aurora; Cheminformatics; Crystal structure; Drug repurposing; Structure based drug design