title: Perspective on computational and structural aspects of kinase discovery from IPK2014.
abstract: Recent advances in understanding the activity and selectivity of kinase inhibitors and their relationships to protein structure are presented. Conformational selection in kinases is studied from empirical, data-driven and simulation approaches. Ligand binding and its affinity are, in many cases, determined by the predetermined active and inactive conformation of kinases. Binding affinity and selectivity predictions highlight the current state of the art and advances in computational chemistry as it applies to kinase inhibitor discovery. Kinome wide inhibitor profiling and cell panel profiling lead to a better understanding of selectivity and allow for target validation and patient tailoring hypotheses. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
authors: Novartis Institutes for BioMedical Research, 5300 Chiron Way, Emeryville, CA 94608-2916, USA.
authors: Eric
authors: E
authors: Martin
authors: Target Discovery Institute and Structural Genomics Consortium, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford OX3 7FZ, UK.
authors: Stefan
authors: S
authors: Knapp
authors: The Norwegian Structural Biology Centre, Department of Chemistry, University of Tromsø, Tromsø, Norway.
authors: Richard A
authors: RA
authors: Engh
authors: Novartis Institutes for BioMedical Research, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland.
authors: Henrik
authors: H
authors: Moebitz
authors: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, DC 1931, Indianapolis, IN 46285, USA.
authors: Thibault
authors: T
authors: Varin
authors: University of Chicago, Dept. of Biochemistry & Molecular Biology, 929 E. 57th St., Chicago 60637, IL, USA.
authors: Benoit
authors: B
authors: Roux
authors: Department of Chemistry, Vanderbilt University, Nashville, TN 37232, USA.
authors: Jens
authors: J
authors: Meiler
authors: Astex Pharmaceuticals, 436 Cambridge Science Park, Milton Road, Cambridge CB4 0QA, United Kingdom.
authors: Valerio
authors: V
authors: Berdini
authors: DiscoveRx Corporation, 42501 Albrae Street, Suite 100, Fremont, CA 94538, USA.
authors: Alexander
authors: A
authors: Baumann
authors: Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, DC 1931, Indianapolis, IN 46285, USA. Electronic address: vieth_michal@lilly.com.
authors: Michal
authors: M
authors: Vieth
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001665:Binding Sites; D000081247:CSK Tyrosine-Protein Kinase; D019295:Computational Biology; D006801:Humans; D011485:Protein Binding; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D011494:Protein Kinases / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D016315:Proto-Oncogene Proteins c-abl / Q000737:chemistry / Q000235:genetics*; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D000081247:CSK Tyrosine-Protein Kinase; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; C000631346:CSK protein, human
keywords: Cancer cell panel profiling; Conformational selection; DFG in–out transition; Kinase inhibition profile; Kinase inhibitor