title: Structure-kinetic relationship study of CDK8/CycC specific compounds.
abstract: In contrast with the very well explored concept of structure-activity relationship, similar studies are missing for the dependency between binding kinetics and compound structure of a protein ligand complex, the structure-kinetic relationship. Here, we present a structure-kinetic relationship study of the cyclin-dependent kinase 8 (CDK8)/cyclin C (CycC) complex. The scaffold moiety of the compounds is anchored in the kinase deep pocket and extended with diverse functional groups toward the hinge region and the front pocket. These variations can cause the compounds to change from fast to slow binding kinetics, resulting in an improved residence time. The flip of the DFG motif ("DMG" in CDK8) to the inactive DFG-out conformation appears to have relatively little influence on the velocity of binding. Hydrogen bonding with the kinase hinge region contributes to the residence time but has less impact than hydrophobic complementarities within the kinase front pocket.
authors: Max-Planck-Institut für Biochemie, D-82152 Martinsried, Germany. schneider@proteros.com
authors: Elisabeth V
authors: EV
authors: Schneider
authors: Jark
authors: J
authors: Böttcher
authors: Robert
authors: R
authors: Huber
authors: Klaus
authors: K
authors: Maskos
authors: Lars
authors: L
authors: Neumann
mesh_terms: D020816:Amino Acid Motifs; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D056745:Cyclin C / Q000737:chemistry*; D056850:Cyclin-Dependent Kinase 8 / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D006860:Hydrogen Bonding; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D012492:Salts / Q000737:chemistry; D013696:Temperature; D013997:Time Factors
chemical_list: D056745:Cyclin C; D008024:Ligands; D012492:Salts; D056850:Cyclin-Dependent Kinase 8
keywords: kinetic profiling; structure-based drug design
references: Biochemistry. 2008 May 20;47(20):5481-92
references: 18412369
references: Nature. 2000 Sep 7;407(6800):102-6
references: 10993082
references: J Mol Biol. 1999 Apr 16;287(5):821-8
references: 10222191
references: EMBO J. 1993 Mar;12(3):849-59
references: 8384554
references: J Med Chem. 2003 Oct 23;46(22):4669-75
references: 14561086
references: Nature. 2008 Sep 25;455(7212):552-6
references: 18794899
references: Drug Discov Today. 2011 Nov;16(21-22):910-3
references: 21946261
references: Mol Cell. 2007 Jul 6;27(1):121-33
references: 17612495
references: Expert Opin Drug Discov. 2008 Dec;3(12):1427-49
references: 23506107
references: J Comput Aided Mol Des. 2009 Aug;23(8):501-11
references: 19533372
references: Chem Biol. 2010 Sep 24;17(9):931-6
references: 20851342
references: J Med Chem. 2003 Oct 23;46(22):4676-86
references: 14561087
references: Mol Cell. 1998 Jul;2(1):43-53
references: 9702190
references: Cell Cycle. 2010 Apr 15;9(8):1551-61
references: 20372077
references: Methods Enzymol. 1997;277:620-33
references: 18488327
references: Acta Crystallogr D Biol Crystallogr. 2010 Jan;66(Pt 1):22-5
references: 20057045
references: Biochim Biophys Acta. 2005 Dec 30;1754(1-2):58-64
references: 16361058
references: Nat Rev Drug Discov. 2006 Sep;5(9):730-9
references: 16888652
references: J Biomol Struct Dyn. 2002 Oct;20(2):141-54
references: 12354066
references: J Med Chem. 2010 Apr 8;53(7):2681-94
references: 20000735
references: Nature. 1995 Jul 27;376(6538):313-20
references: 7630397
references: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17783-8
references: 17095602
references: Nat Chem Biol. 2006 Jul;2(7):358-64
references: 16783341
references: J Am Chem Soc. 2011 Nov 23;133(46):18903-10
references: 21981450
references: Nature. 2010 Dec 23;468(7327):1105-9
references: 21179167
references: Curr Opin Chem Biol. 2010 Aug;14(4):467-74
references: 20663707
references: J Mol Biol. 1999 Feb 5;285(5):2177-98
references: 9925793
references: J Exp Clin Cancer Res. 2011 Nov 22;30:109
references: 22104393
references: J Mol Biol. 2011 Sep 16;412(2):251-66
references: 21806996
references: Nat Struct Biol. 2002 Apr;9(4):268-72
references: 11896401
references: Transcription. 2010 Jul-Aug;1(1):4-12
references: 21327159
references: Cell. 2002 May 3;109(3):275-82
references: 12015977
references: Nature. 2008 Sep 25;455(7212):547-51
references: 18794900
references: Biochim Biophys Acta. 2010 Mar;1804(3):511-9
references: 19822225
references: Bioorg Med Chem. 2010 Aug 1;18(15):5738-48
references: 20621496
references: Acta Crystallogr D Biol Crystallogr. 2010 Feb;66(Pt 2):125-32
references: 20124692
references: Eur J Biochem. 2004 Mar;271(5):1004-14
references: 15009212
references: Cancer Res. 2009 Oct 15;69(20):7899-901
references: 19808961
references: IDrugs. 2010 Jul;13(7):457-66
references: 20582870
references: Methods Enzymol. 2011;493:299-320
references: 21371596
references: Nat Struct Mol Biol. 2010 Feb;17(2):194-201
references: 20098423
references: J Am Chem Soc. 2009 Sep 23;131(37):13286-96
references: 19572644
references: J Mol Biol. 1974 Oct 15;89(1):73-101
references: 4475115