Protein Structure Similarity as Guiding Principle for Combinatorial Library Design

Abstract Proteins are modularly built from a limited set of approximately 1000 structural domains. The evolutionary relationship within a domain family suggests that the knowledge about a common fold structure can be exploited for the design of small molecule libraries in the development of inhibitors and ligands. This principle has been used for the synthesis of inhibitors for kinases sharing the same fold. It can also be applied for proteins which share the same fold architecture yet belong to different functional classes. Bestatin – originally known as an aminopeptidase inhibitor – was employed as guiding structure for the development of leukotriene A4 hydrolase inhibitors. A combinatorial approach helped to identify inhibitors for sulfotransferases which share structural similarity with nucleotide kinases using a kinase inhibitor core structure as guiding principle.

[1]  Michael Y. Galperin,et al.  The COG database: new developments in phylogenetic classification of proteins from complete genomes , 2001, Nucleic Acids Res..

[2]  E. Koonin,et al.  Emergence of diverse biochemical activities in evolutionarily conserved structural scaffolds of proteins. , 2003, Current opinion in chemical biology.

[3]  Herbert Waldmann,et al.  From protein domains to drug candidates-natural products as guiding principles in the design and synthesis of compound libraries. , 2002, Angewandte Chemie.

[4]  K. Chapman,et al.  Combinatorial synthesis of 3-(amidoalkyl) and 3-(aminoalkyl)-2-arylindole derivatives: discovery of potent ligands for a variety of G-protein coupled receptors. , 2002, Bioorganic & medicinal chemistry letters.

[5]  N S Gray,et al.  Discovery of estrogen sulfotransferase inhibitors from a purine library screen. , 2001, Journal of medicinal chemistry.

[6]  R Breinbauer,et al.  From protein domains to drug candidates--natural products as guiding principles in compound library design and synthesis. , 2003, Ernst Schering Research Foundation workshop.

[7]  B. E. Evans,et al.  Methods for drug discovery: development of potent, selective, orally effective cholecystokinin antagonists. , 1988, Journal of medicinal chemistry.

[8]  R. Spencer,et al.  High-throughput screening of historic collections: observations on file size, biological targets, and file diversity. , 1998, Biotechnology and bioengineering.

[9]  P. Schultz,et al.  Synthesis and application of functionally diverse 2,6,9-trisubstituted purine libraries as CDK inhibitors. , 1999, Chemistry & biology.

[10]  M.-Q. Zhang.  Leukotrine A4 hydrolase: a new target for anti-imflammatory intervention. , 1997 .

[11]  A. Ghose,et al.  A knowledge-based approach in designing combinatorial or medicinal chemistry libraries for drug discovery. 1. A qualitative and quantitative characterization of known drug databases. , 1999, Journal of combinatorial chemistry.

[12]  A Danchin,et al.  From protein sequence to function. , 1999, Current opinion in structural biology.

[13]  L. Pedersen,et al.  The Sulfuryl Transfer Mechanism , 1998, The Journal of Biological Chemistry.

[14]  John P. Overington,et al.  Insights into protein function through large-scale computational analysis of sequence and structure. , 2001, Trends in biotechnology.

[15]  B. Stockwell.  Chemical genetics: ligand-based discovery of gene function , 2000, Nature Reviews Genetics.

[16]  Anthony C. Bishop,et al.  Discovery of Carbohydrate Sulfotransferase Inhibitors from a Kinase‐Directed Library , 2000 .

[17]  F. Fitzpatrick,et al.  Leukotriene A4 hydrolase. Inhibition by bestatin and intrinsic aminopeptidase activity establish its functional resemblance to metallohydrolase enzymes. , 1991, The Journal of biological chemistry.

[18]  L. Pedersen,et al.  Crystal structure of estrogen sulphotransferase , 1997, Nature Structural Biology.

[19]  H. Waldmann,et al.  Natural product derived receptor tyrosine kinase inhibitors: identification of IGF1R, Tie-2, and VEGFR-3 inhibitors. , 2002, Angewandte Chemie.

[20]  J. Mason,et al.  Diversity assessment. , 1999, Current opinion in chemical biology.

[21]  P. Green,et al.  Ancient conserved regions in new gene sequences and the protein databases. , 1993, Science.

[22]  M J Sternberg,et al.  Supersites within superfolds. Binding site similarity in the absence of homology. , 1998, Journal of molecular biology.

[23]  A. Murzin.  How far divergent evolution goes in proteins. , 1998, Current opinion in structural biology.

[24]  C. Ponting,et al.  On the evolution of protein folds: are similar motifs in different protein folds the result of convergence, insertion, or relics of an ancient peptide world? , 2001, Journal of structural biology.

[25]  Peter J. Alaimo,et al.  Chemical genetic approaches for the elucidation of signaling pathways. , 2001, Current opinion in chemical biology.

[26]  G. Schneider,et al.  Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries. , 2001, Journal of combinatorial chemistry.

[27]  Ajay,et al.  Recognizing molecules with drug-like properties. , 1999, Current opinion in chemical biology.

[28]  H. Kubinyi,et al.  A scoring scheme for discriminating between drugs and nondrugs. , 1998, Journal of medicinal chemistry.

[29]  W. Guida,et al.  The art and practice of structure‐based drug design: A molecular modeling perspective , 1996, Medicinal research reviews.

[30]  E V Koonin,et al.  Estimating the number of protein folds and families from complete genome data. , 2000, Journal of molecular biology.

[31]  L. Holm,et al.  Unification of protein families. , 1998, Current opinion in structural biology.

[32]  H. Waldmann,et al.  Natural products are biologically validated starting points in structural space for compound library development: solid-phase synthesis of dysidiolide-derived phosphatase inhibitors. , 2002, Angewandte Chemie.

[33]  P. Furet,et al.  Total synthesis and biological evaluation of the nakijiquinones. , 2001, Journal of the American Chemical Society.

[34]  C. Chothia.  Proteins. One thousand families for the molecular biologist. , 1992, Nature.

[35]  D. T. Jones,et al.  Protein folds: towards understanding folding from inspection of native structures. , 1995, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[36]  Peter G Schultz,et al.  A potent and highly selective sulfotransferase inhibitor. , 2002, Journal of the American Chemical Society.

[37]  Jesper Z. Haeggström,et al.  Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation , 2001, Nature Structural Biology.

[38]  Ajay,et al.  Can we learn to distinguish between "drug-like" and "nondrug-like" molecules? , 1998, Journal of medicinal chemistry.

[39]  A Golebiowski,et al.  Lead compounds discovered from libraries. , 2001, Current opinion in chemical biology.

[40]  P. Babbitt,et al.  Divergent evolution of enzymatic function: mechanistically diverse superfamilies and functionally distinct suprafamilies. , 2001, Annual review of biochemistry.

[41]  S H Kim,et al.  Exploiting chemical libraries, structure, and genomics in the search for kinase inhibitors. , 1998, Science.

[42]  C. Orengo,et al.  Evolution of protein function, from a structural perspective. , 1999, Current opinion in chemical biology.

[43]  P. Schultz,et al.  Purine‐Based Inhibitors of Inositol‐1,4,5‐trisphosphate‐3‐kinase , 2002, Chembiochem : a European journal of chemical biology.

[44]  C. Ponting,et al.  Evolution of domain families. , 2000, Advances in protein chemistry.

[45]  M. Murcko,et al.  Chemogenomic approaches to drug discovery. , 2001, Current opinion in chemical biology.

[46]  Peter G. Schultz,et al.  A Structure-Based Library Approach to Kinase Inhibitors , 1996 .

[47]  I. Ollmann,et al.  Investigation of the inhibition of leukotriene A4 hydrolase. , 1995, Bioorganic & medicinal chemistry.

[48]  C. Chothia.  One thousand families for the molecular biologist , 1992, Nature.

[49]  Ruben Recabarren,et al.  Estimating the total number of protein folds , 1999, Proteins.

[50]  E. Koonin,et al.  The structure of the protein universe and genome evolution , 2002, Nature.