title: Structure-based CoMFA and CoMSIA study of indolinone inhibitors of PDK1.
abstract: Phosphoinositide-dependent protein kinase-1 (PDK1) is a Ser/Thr kinase which phosphorylates and activates members of the AGC kinase group known to control processes such as tumor cell growth, protection from apoptosis, and tumor angiogenesis. In this paper, CoMFA and CoMSIA studies were carried out on a training set of 56 conformationally rigid indolinone inhibitors of PDK1. Predictive 3D QSAR models, established using atom fit alignment rule based on crystallographic-bound conformation, had cross-validated (r(cv)(2)) values of 0.738 and 0.816 and non-cross-validated (r(ncv)(2)) values of 0.912 and 0.949 for CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models was determined using a test set of 14 compounds, which gave predictive correlation coefficients (r(pred)(2)) of 0.865 and 0.837, respectively. Structure-based interpretation of the CoMFA and CoMSIA field properties provided further insights for the rational design of new PDK1 inhibitors.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Jamaica, NY 11439, USA.
authors.forename: Kirandeep
authors.initials: K
authors.lastname: Kaur
authors.forename: Tanaji T
authors.initials: TT
authors.lastname: Talele
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D007211:Indoles / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; C057812:indoline; D064413:3-Phosphoinositide-Dependent Protein Kinases; D017346:Protein Serine-Threonine Kinases
references.citation: J Biol Chem. 1998 May 29;273(22):13375-8
references.pmid: 9593664
references.citation: Cell Signal. 2002 Apr;14(4):285-95
references.pmid: 11858936
references.citation: Bioorg Med Chem Lett. 2007 Jul 15;17(14):3814-8
references.pmid: 17531483
references.citation: J Med Chem. 1994 Nov 25;37(24):4130-46
references.pmid: 7990113
references.citation: Cell. 2000 Oct 13;103(2):211-25
references.pmid: 11057895
references.citation: Cell. 2002 May 3;109(3):275-82
references.pmid: 12015977
references.citation: EMBO J. 2000 Mar 1;19(5):979-88
references.pmid: 10698939
references.citation: Nat Struct Biol. 2002 Dec;9(12):940-4
references.pmid: 12434148
references.citation: Bioorg Med Chem Lett. 2007 Jul 15;17(14):3819-25
references.pmid: 17544272
references.citation: Biochem Soc Trans. 2001 Nov;29(Pt 6):860-3
references.pmid: 11709088
references.citation: Trends Biochem Sci. 2001 Nov;26(11):657-64
references.pmid: 11701324
references.citation: J Am Chem Soc. 1988 Aug 1;110(18):5959-67
references.pmid: 22148765
references.citation: Science. 2002 May 31;296(5573):1655-7
references.pmid: 12040186
references.citation: Mol Cell. 2002 Jun;9(6):1227-40
references.pmid: 12086620
references.citation: Nat Rev Mol Cell Biol. 2001 Oct;2(10):760-8
references.pmid: 11584303
references.citation: J Comput Aided Mol Des. 1999 Jan;13(1):35-49
references.pmid: 10087498
references.citation: J Mol Biol. 1994 Mar 25;237(2):212-35
references.pmid: 8126735
references.citation: Curr Biol. 1997 Apr 1;7(4):261-9
references.pmid: 9094314
references.citation: Semin Cell Dev Biol. 2004 Apr;15(2):161-70
references.pmid: 15209375
references.citation: Front Biosci. 2002 Apr 01;7:d886-902
references.pmid: 11897568
references.citation: EMBO J. 2002 Aug 15;21(16):4219-28
references.pmid: 12169624