Design of compound libraries for fragment screening

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.

[1]  Jennifer R Krumrine,et al.  Statistical tools for virtual screening. , 2005, Journal of medicinal chemistry.

[2]  C. Lipinski,et al.  pKa, Log P and MedChem CLOGP Fragment Values of Acidic Heterocyclic Potential Bioisosteres , 1991 .

[3]  M. Congreve,et al.  A 'rule of three' for fragment-based lead discovery? , 2003, Drug discovery today.

[4]  Daniel A Erlanson,et al.  Tethering: fragment-based drug discovery. , 2004, Annual review of biophysics and biomolecular structure.

[5]  Karen N. Allen,et al.  An Experimental Approach to Mapping the Binding Surfaces of Crystalline Proteins , 1996 .

[6]  M. Randal,et al.  Potent small-molecule binding to a dynamic hot spot on IL-2. , 2003, Journal of the American Chemical Society.

[7]  Jon Read,et al.  Structure-based design of protein tyrosine phosphatase-1B inhibitors. , 2005, Bioorganic & medicinal chemistry letters.

[8]  Tudor I. Oprea,et al.  The Design of Leadlike Combinatorial Libraries. , 1999, Angewandte Chemie.

[9]  J. Andrew Grant,et al.  Small Molecule Shape-Fingerprints , 2005, J. Chem. Inf. Model..

[10]  Karl Edman,et al.  Novel prostaglandin D synthase inhibitors generated by fragment-based drug design. , 2008, Journal of medicinal chemistry.

[11]  Darren R. Flower,et al.  On the Properties of Bit String-Based Measures of Chemical Similarity , 1998, J. Chem. Inf. Comput. Sci..

[12]  Glyn Williams,et al.  Fragment-based screening using X-ray crystallography and NMR spectroscopy. , 2007, Current opinion in chemical biology.

[13]  Ramaswamy Nilakantan,et al.  A fresh look at pharmaceutical screening library design. , 2003, Drug discovery today.

[14]  P. Hajduk,et al.  Discovery of a potent inhibitor of the antiapoptotic protein Bcl-xL from NMR and parallel synthesis. , 2006, Journal of medicinal chemistry.

[15]  W. Jencks,et al.  On the attribution and additivity of binding energies. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Jens Sadowski,et al.  Structure Modification in Chemical Databases , 2005 .

[17]  Richard O. Roblin,et al.  Studies in Chemotherapy. VII. A Theory of the Relation of Structure to Activity of Sulfanilamide Type Compounds1 , 1942 .

[18]  Thierry Kogej,et al.  Multifingerprint Based Similarity Searches for Targeted Class Compound Selection , 2006, J. Chem. Inf. Model..

[19]  Mark Whittaker,et al.  Fragment screening by biochemical assay , 2006, Expert opinion on drug discovery.

[20]  D. Kostrewa,et al.  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. , 2000, Journal of medicinal chemistry.

[21]  Robin Taylor,et al.  Simulation Analysis of Experimental Design Strategies for Screening Random Compounds as Potential New Drugs and Agrochemicals , 1995, J. Chem. Inf. Comput. Sci..

[22]  Robert D Clark,et al.  Neighborhood behavior: a useful concept for validation of "molecular diversity" descriptors. , 1996, Journal of medicinal chemistry.

[23]  Edgar Jacoby,et al.  Library design for fragment based screening. , 2005, Current topics in medicinal chemistry.

[24]  Michael F. Lynch,et al.  Analysis of structural characteristics of chemical compounds in a large computer-based file. Part II. Atom-centred fragments , 1970 .

[25]  Ajay,et al.  The SHAPES strategy: an NMR-based approach for lead generation in drug discovery. , 1999, Chemistry & biology.

[26]  Gianni Chessari,et al.  Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency. , 2007, Journal of medicinal chemistry.

[27]  M. Karplus,et al.  Functionality maps of binding sites: A multiple copy simultaneous search method , 1991, Proteins.

[29]  W. Delano.  Unraveling hot spots in binding interfaces: progress and challenges. , 2002, Current opinion in structural biology.

[30]  N. Blomberg,et al.  An integrated approach to fragment-based lead generation: philosophy, strategy and case studies from AstraZeneca's drug discovery programmes. , 2007, Current topics in medicinal chemistry.

[31]  Hans-Joachim Böhm,et al.  The computer program LUDI: A new method for the de novo design of enzyme inhibitors , 1992, J. Comput. Aided Mol. Des..

[32]  Darko Butina,et al.  Unsupervised Data Base Clustering Based on Daylight's Fingerprint and Tanimoto Similarity: A Fast and Automated Way To Cluster Small and Large Data Sets , 1999, J. Chem. Inf. Comput. Sci..

[33]  L. A. Bassalygo,et al.  Hash codes , 1997, Proceedings of IEEE International Symposium on Information Theory.

[34]  A. Bogan,et al.  Anatomy of hot spots in protein interfaces. , 1998, Journal of molecular biology.

[35]  P. Hajduk,et al.  Discovering High-Affinity Ligands for Proteins: SAR by NMR , 1996, Science.

[36]  R. J. Herr,et al.  5-Substituted-1H-tetrazoles as carboxylic acid isosteres: medicinal chemistry and synthetic methods. , 2002, Bioorganic & medicinal chemistry.

[37]  M. Congreve,et al.  Recent developments in fragment-based drug discovery. , 2008, Journal of medicinal chemistry.

[38]  Mark Whittaker,et al.  Fragment-based activity space: smaller is better. , 2008, Current opinion in chemical biology.

[39]  Rutger H A Folmer,et al.  Discovery of a novel warhead against beta-secretase through fragment-based lead generation. , 2007, Journal of medicinal chemistry.

[40]  Andrew R. Leach,et al.  Molecular Complexity and Its Impact on the Probability of Finding Leads for Drug Discovery , 2001, J. Chem. Inf. Comput. Sci..

[41]  T. O'Brien,et al.  Fragment-based drug discovery. , 2004, Journal of medicinal chemistry.

[42]  P. Hajduk,et al.  A decade of fragment-based drug design: strategic advances and lessons learned , 2007, Nature Reviews Drug Discovery.

[43]  Brian Dymock,et al.  Design and Characterization of Libraries of Molecular Fragments for Use in NMR Screening against Protein Targets , 2004, J. Chem. Inf. Model..

[44]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[45]  Christopher W Murray,et al.  Fragment-based lead discovery using X-ray crystallography. , 2005, Journal of medicinal chemistry.

[46]  J. A. Grant,et al.  A Gaussian Description of Molecular Shape , 1995 .