title: Design of a multi-purpose fragment screening library using molecular complexity and orthogonal diversity metrics.
abstract: Fragment Based Drug Discovery (FBDD) continues to advance as an efficient and alternative screening paradigm for the identification and optimization of novel chemical matter. To enable FBDD across a wide range of pharmaceutical targets, a fragment screening library is required to be chemically diverse and synthetically expandable to enable critical decision making for chemical follow-up and assessing new target druggability. In this manuscript, the Pfizer fragment library design strategy which utilized multiple and orthogonal metrics to incorporate structure, pharmacophore and pharmacological space diversity is described. Appropriate measures of molecular complexity were also employed to maximize the probability of detection of fragment hits using a variety of biophysical and biochemical screening methods. In addition, structural integrity, purity, solubility, fragment and analog availability as well as cost were important considerations in the selection process. Preliminary analysis of primary screening results for 13 targets using NMR Saturation Transfer Difference (STD) indicates the identification of uM-mM hits and the uniqueness of hits at weak binding affinities for these targets.
authors: Pfizer Global Research and Development (PGRD), Groton, CT 06340, USA. wlau64p@gmail.com
authors: Wan F
authors: WF
authors: Lau
authors: Jane M
authors: JM
authors: Withka
authors: David
authors: D
authors: Hepworth
authors: Thomas V
authors: TV
authors: Magee
authors: Yuhua J
authors: YJ
authors: Du
authors: Gregory A
authors: GA
authors: Bakken
authors: Michael D
authors: MD
authors: Miller
authors: Zachary S
authors: ZS
authors: Hendsch
authors: Venkataraman
authors: V
authors: Thanabal
authors: Steve A
authors: SA
authors: Kolodziej
authors: Li
authors: L
authors: Xing
authors: Qiyue
authors: Q
authors: Hu
authors: Lakshmi S
authors: LS
authors: Narasimhan
authors: Robert
authors: R
authors: Love
authors: Maura E
authors: ME
authors: Charlton
authors: Samantha
authors: S
authors: Hughes
authors: Willem P
authors: WP
authors: van Hoorn
authors: James E
authors: JE
authors: Mills
references: J Med Chem. 2007 May 17;50(10):2293-6
references: 17451234
references: Magn Reson Chem. 2004 Jun;42(6):485-9
references: 15137040
references: Curr Opin Chem Biol. 2007 Oct;11(5):485-93
references: 17851109
references: J Comput Aided Mol Des. 1996 Dec;10(6):607-22
references: 9007693
references: Science. 1996 Nov 29;274(5292):1531-4
references: 8929414
references: J Chem Inf Comput Sci. 2004 Nov-Dec;44(6):2157-66
references: 15554686
references: J Chem Inf Comput Sci. 2001 May-Jun;41(3):856-64
references: 11410068
references: Curr Top Med Chem. 2007;7(16):1630-42
references: 17979772
references: J Comput Aided Mol Des. 2009 Aug;23(8):513-25
references: 19283339
references: J Med Chem. 2008 Apr 24;51(8):2432-8
references: 18380424
references: Comb Chem High Throughput Screen. 2002 Dec;5(8):583-90
references: 12470255
references: J Biomol Screen. 2007 Jun;12(4):457-63
references: 17379856
references: J Chem Inf Comput Sci. 2002 Nov-Dec;42(6):1273-80
references: 12444722
references: Nat Biotechnol. 2005 Feb;23(2):201-7
references: 15685167
references: J Chem Inf Model. 2005 Sep-Oct;45(5):1237-43
references: 16180900
references: Drug Discov Today. 2001 Feb 1;6(3):133-140
references: 11165186
references: J Med Chem. 2004 Jul 1;47(14):3463-82
references: 15214773
references: Nat Rev Drug Discov. 2010 Jan;9(1):23-7
references: 19960014
references: Curr Top Med Chem. 2007;7(16):1568-81
references: 17979768
references: J Biomol NMR. 2001 Dec;21(4):349-59
references: 11824754
references: Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
references: 11259830
references: J Comput Aided Mol Des. 2009 Aug;23(8):603-20
references: 19495994
references: Nat Biotechnol. 2006 Jul;24(7):805-15
references: 16841068
references: Curr Top Med Chem. 2007;7(16):1600-29
references: 17979771
references: J Chem Inf Model. 2005 Jan-Feb;45(1):177-82
references: 15667143
references: Curr Top Med Chem. 2005;5(8):751-62
references: 16101415
references: Drugs R D. 2008;9(4):217-27
references: 18588353
references: J Med Chem. 2000 Oct 5;43(20):3714-7
references: 11020286
references: J Med Chem. 2006 Feb 23;49(4):1346-55
references: 16480269
references: J Med Chem. 1996 Jul 19;39(15):2887-93
references: 8709122
references: Drug Discov Today. 2003 Oct 1;8(19):876-7
references: 14554012
references: J Chem Inf Comput Sci. 2003 Mar-Apr;43(2):391-405
references: 12653501
references: Expert Opin Drug Discov. 2006 Aug;1(3):225-36
references: 23495844
references: J Comput Aided Mol Des. 2009 Oct;23(10):725-36
references: 19593647
references: Drug Discov Today. 2005 Jul 15;10(14):987-92
references: 16023057
references: J Chem Inf Comput Sci. 2000 Nov-Dec;40(6):1302-14
references: 11128088
references: Drug Discov Today. 2004 May 15;9(10):430-1
references: 15109945
references: J Med Chem. 2008 Jul 10;51(13):3661-80
references: 18457385
references: Drug Discov Today. 2005 Dec;10(23-24):1675-82
references: 16376828
references: J Med Chem. 2005 Jan 27;48(2):403-13
references: 15658854
references: Pharm Res. 2002 Apr;19(4):497-503
references: 12033386
references: Angew Chem Int Ed Engl. 1999 Dec 16;38(24):3743-3748
references: 10649345
references: Curr Opin Drug Discov Devel. 2007 May;10(3):289-97
references: 17554855