Design of compound libraries for fragment screening

被引：58

作者：

Blomberg, Niklas ^{[2
]}

Cosgrove, David A. ^{[1
]}

Kenny, Peter W. ^{[1
]}

Kolmodin, Karin ^{[3
]}

机构：

[1] AstraZeneca R&D Alderley Pk, Macclesfield SK10 4TG, Cheshire, England

[2] AstraZeneca R&D, S-43183 Molndal, Sweden

[3] AstraZeneca R&D Sodertalje, S-15185 Sodertalje, Sweden

来源：

JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN | 2009年 / 23卷 / 08期

关键词：

Fragment based; Fragment based drug discovery; Fragment based lead generation; Fragment screening; FBDD; FBLG; NMR screening; Screening library; Library design; Molecular complexity; Molecular similarity; Neighborhood; Fingerprint; Foyfi; Flush; Bigpicker; Filter; Leatherface; SMARTS; Solubility; LEAD GENERATION; BETA-SECRETASE; BINDING-SITES; HOT-SPOTS; DISCOVERY; NMR; INHIBITORS; VALIDATION; SIMILARITY; STRATEGY;

D O I：

10.1007/s10822-009-9264-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Approaches to the design of libraries for fragment screening are illustrated with reference to a 20 k generic fragment screening library and a 1.2 k generic NMR screening library. Tools and methods for library design that have been developed within AstraZeneca are described, including Foyfi fingerprints and the Flush program for neighborhood characterization. It will be shown how Flush and the BigPicker, which selects maximally diverse sets of compounds, are used to apply the Core and Layer method for library design. Approaches to partitioning libraries into cocktails are also described.

引用

页码：513 / 525

页数：13

共 52 条

[1] ANALYSIS OF STRUCTURAL CHARACTERISTICS OF CHEMICAL COMPOUNDS IN A LARGE COMPUTER-BASED FILE .2. ATOM-CENTRED FRAGMENTS [J].

ADAMSON, GW ;

LYNCH, MF ;

TOWN, WG .

JOURNAL OF THE CHEMICAL SOCIETY C-ORGANIC, 1971, (22) :3702-&

[2] An integrated approach to fragment-based lead generation: Philosophy, strategy and case studies from AstraZeneca's drug discovery programmes [J].

Albert, Jeffrey S. ;

Blomberg, Niklas ;

Breeze, Alexander L. ;

Brown, Alastair J. H. ;

Burrows, Jeremy N. ;

Edwards, Philip D. ;

Folmer, Rutger H. A. ;

Geschwindner, Stefan ;

Griffen, Ed J. ;

Kenny, Peter W. ;

Nowak, Thorsten ;

Olsson, Lise-Lotte ;

Sanganee, Hitesh ;

Shapiro, Adam B. .

CURRENT TOPICS IN MEDICINAL CHEMISTRY, 2007, 7 (16) :1600-1629

[3] An experimental approach to mapping the binding surfaces of crystalline proteins [J].

Allen, KN ;

Bellamacina, CR ;

Ding, XC ;

Jeffery, CJ ;

Mattos, C ;

Petsko, GA ;

Ringe, D .

JOURNAL OF PHYSICAL CHEMISTRY, 1996, 100 (07) :2605-2611

[4]

[Anonymous], ROCS OPENEYE SCI SOF

[5]

[Anonymous], SMARTS THEOR MAN, P92677

[6] Fragment screening by biochemical assay [J].

Barker, John ;

Courtney, Steve ;

Hesterkamp, Thomas ;

Ullmann, Dirk ;

Whittaker, Mark .

EXPERT OPINION ON DRUG DISCOVERY, 2006, 1 (03) :225-236

[7] Design and characterization of libraries of molecular fragments for use in NMR screening against protein targets [J].

Baurin, N ;

Aboul-Ela, F ;

Barril, X ;

Davis, B ;

Drysdale, M ;

Dymock, B ;

Finch, H ;

Fromont, C ;

Richardson, C ;

Simmonite, H ;

Hubbard, RE .

JOURNAL OF CHEMICAL INFORMATION AND COMPUTER SCIENCES, 2004, 44 (06) :2157-2166

[8] Studies in chemotherapy. VII. A theory of the relation of structure to activity of sulfanilamide type compounds [J].

Bell, PH ;

Roblin, RO .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1942, 64 :2905-2917

[9] Structure-based design of protein tyrosine phosphatase-1B inhibitors [J].

Black, E ;

Breed, J ;

Breeze, AL ;

Embrey, K ;

Garcia, R ;

Gero, TW ;

Godfrey, L ;

Kenny, PW ;

Morley, AD ;

Minshull, CA ;

Pannifer, AD ;

Read, J ;

Rees, A ;

Russell, DJ ;

Toader, D ;

Tucker, J .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (10) :2503-2507

[10] Novel inhibitors of DNA gyrase: 3D structure based biased needle screening, hit validation by biophysical methods, and 3D guided optimization. A promising alternative to random screening [J].

Boehm, HJ ;

Boehringer, M ;

Bur, D ;

Gmuender, H ;

Huber, W ;

Klaus, W ;

Kostrewa, D ;

Kuehne, H ;

Luebbers, T ;

Meunier-Keller, N .

JOURNAL OF MEDICINAL CHEMISTRY, 2000, 43 (14) :2664-2674

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