Exploring biology with small organic molecules

Small organic molecules have proven to be invaluable tools for investigating biological systems, but there is still much to learn from their use. To discover and to use more effectively new chemical tools to understand biology, strategies are needed that allow us to systematically explore ‘biological-activity space’. Such strategies involve analysing both protein binding of, and phenotypic responses to, small organic molecules. The mapping of biological-activity space using small molecules is akin to mapping the stars — uncharted territory is explored using a system of coordinates that describes where each new feature lies.

[1]  N. Munakata.  [Genetics of Caenorhabditis elegans]. , 1989, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[2]  L. Hartwell,et al.  Twenty-five years of cell cycle genetics. , 1991, Genetics.

[3]  S. N. Timasheff,et al.  Physical and spectroscopic methods for the evaluation of the interactions of antimitotic agents with tubulin. , 1991, Pharmacology & therapeutics.

[4]  S. Schreiber,et al.  Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. S. Johnson,et al.  An Information-Intensive Approach to the Molecular Pharmacology of Cancer , 1997, Science.

[6]  J H Lakey,et al.  Measuring protein-protein interactions. , 1998, Current opinion in structural biology.

[7]  S. Schreiber.  Chemical genetics resulting from a passion for synthetic organic chemistry. , 1998, Bioorganic & medicinal chemistry.

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

[9]  H O Villar,et al.  Protein affinity map of chemical space. , 1998, Journal of chromatography. B, Biomedical sciences and applications.

[10]  R. Misra.  Modern drug development from traditional medicinal plants using radioligand receptor‐binding assays , 1998, Medicinal research reviews.

[11]  Thomas Lengauer,et al.  Evaluation of the FLEXX incremental construction algorithm for protein–ligand docking , 1999, Proteins.

[12]  L Xue,et al.  Molecular scaffold-based design and comparison of combinatorial libraries focused on the ATP-binding site of protein kinases. , 1999, Journal of molecular graphics & modelling.

[13]  Stuart L. Schreiber,et al.  Printing Small Molecules as Microarrays and Detecting Protein−Ligand Interactions en Masse , 1999 .

[14]  H. Bosshard,et al.  Isothermal titration calorimetry and differential scanning calorimetry as complementary tools to investigate the energetics of biomolecular recognition , 1999, Journal of molecular recognition : JMR.

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

[16]  S. Schreiber,et al.  Target-oriented and diversity-oriented organic synthesis in drug discovery. , 2000, Science.

[17]  B. Stockwell,et al.  Frontiers in chemical genetics. , 2000, Trends in biotechnology.

[18]  D. Sabatini,et al.  Microarrays of cells expressing defined cDNAs , 2001, Nature.

[19]  Recent advances in NMR: expanding its role in rational drug design. , 2001, Current medicinal chemistry.

[20]  H Osada,et al.  Synthesis of a tetronic acid library focused on inhibitors of tyrosine and dual-specificity protein phosphatases and its evaluation regarding VHR and cdc25B inhibition. , 2001, Journal of medicinal chemistry.

[21]  G. Dreyfuss,et al.  A cell system with targeted disruption of the SMN gene: functional conservation of the SMN protein and dependence of Gemin2 on SMN. , 2001, The Journal of biological chemistry.

[22]  M. Gerstein,et al.  Global Analysis of Protein Activities Using Proteome Chips , 2001, Science.

[23]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[24]  K. Lam,et al.  Peptide and small molecule microarray for high throughput cell adhesion and functional assays. , 2001, Bioconjugate chemistry.

[25]  T. Tuschl,et al.  Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells , 2001, Nature.

[26]  Todd J. A. Ewing,et al.  DOCK 4.0: Search strategies for automated molecular docking of flexible molecule databases , 2001, J. Comput. Aided Mol. Des..

[27]  P. Schultz,et al.  Profiling protein function with small molecule microarrays , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[28]  Y. Lazebnik,et al.  Confirming Specificity of RNAi in Mammalian Cells , 2002, Science's STKE.

[29]  Marshall M Siegel.  Early discovery drug screening using mass spectrometry. , 2002, Current topics in medicinal chemistry.

[30]  Irwin D Kuntz,et al.  Small molecule affinity fingerprinting. A tool for enzyme family subclassification, target identification, and inhibitor design. , 2002, Chemistry & biology.

[31]  Günter Gauglitz,et al.  Label-free parallel screening of combinatorial triazine libraries using reflectometric interference spectroscopy. , 2002, Analytical chemistry.

[32]  Thomas Tuschl,et al.  Expanding small RNA interference , 2002, Nature Biotechnology.

[33]  S. Schreiber,et al.  Pathway development and pilot library realization in diversity-oriented synthesis: exploring Ferrier and Pauson-Khand reactions on a glycal template. , 2002, Chemistry & biology.

[34]  Jürgen Bajorath,et al.  Integration of virtual and high-throughput screening , 2002, Nature Reviews Drug Discovery.

[35]  G. Hannon.  RNA interference : RNA , 2002 .

[36]  D. Goodsell,et al.  Automated docking to multiple target structures: Incorporation of protein mobility and structural water heterogeneity in AutoDock , 2002, Proteins.

[37]  Gavin MacBeath,et al.  Protein microarrays and proteomics , 2002, Nature Genetics.

[38]  Gregory J. Hannon,et al.  Insight Review Articles , 2022 .

[39]  Jocelyn Côté,et al.  A protein-domain microarray identifies novel protein-protein interactions. , 2002, The Biochemical journal.

[40]  David E Root,et al.  Global analysis of large-scale chemical and biological experiments. , 2002, Current opinion in drug discovery & development.

[41]  B. Stockwell.  Chemical Genetic Screening Approaches to Neurobiology , 2002, Neuron.

[42]  Ravi Kapur,et al.  Fluorescence imaging and engineered biosensors: functional and activity-based sensing using high content screening. , 2002, Annals of the New York Academy of Sciences.

[43]  D. Vetter.  Chemical microarrays, fragment diversity, label‐free imaging by plasmon resonance—a chemical genomics approach , 2002, Journal of cellular biochemistry. Supplement.

[44]  Stuart L. Schreiber,et al.  Dissecting glucose signalling with diversity-oriented synthesis and small-molecule microarrays , 2002, Nature.

[45]  Ravi Kapur,et al.  Fluorescence Imaging and Engineered Biosensors , 2002 .

[46]  G. Gauglitz,et al.  Development of an assay for label-free high-throughput screening of thrombin inhibitors by use of reflectometric interference spectroscopy , 2002, Analytical and bioanalytical chemistry.

[47]  Playing with the pieces , 2003, Nature.

[48]  A. Keating,et al.  Comprehensive Identification of Human bZIP Interactions with Coiled-Coil Arrays , 2003, Science.

[49]  D. Fabbro,et al.  Discovery of a potent and selective protein kinase CK2 inhibitor by high-throughput docking. , 2003, Journal of medicinal chemistry.

[50]  J. Homola.  Present and future of surface plasmon resonance biosensors , 2003, Analytical and bioanalytical chemistry.

[51]  Pamela A. Silver,et al.  A chemical genetic screen identifies inhibitors of regulated nuclear export of a Forkhead transcription factor in PTEN-deficient tumor cells. , 2003, Cancer cell.

[52]  William C Hahn,et al.  Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. , 2003, Cancer cell.

[53]  M. Snyder,et al.  Recent developments in analytical and functional protein microarrays. , 2003, Current opinion in molecular therapeutics.

[54]  Chen Xu,et al.  Identification of novel inhibitors of BCR-ABL tyrosine kinase via virtual screening. , 2003, Bioorganic & medicinal chemistry letters.

[55]  B. Stockwell,et al.  Biological mechanism profiling using an annotated compound library. , 2003, Chemistry & biology.

[56]  Stuart L. Schreiber,et al.  The small-molecule approach to biology , 2003 .

[57]  B. Shoichet,et al.  Identification and prediction of promiscuous aggregating inhibitors among known drugs. , 2003, Journal of medicinal chemistry.

[58]  David R Spring,et al.  Diversity-oriented synthesis; a challenge for synthetic chemists. , 2003, Organic & biomolecular chemistry.

[59]  Stuart L Schreiber,et al.  Generating Diverse Skeletons of Small Molecules Combinatorially , 2003, Science.

[60]  K. Ervin,et al.  Development and application of fluorescence polarization assays in drug discovery. , 2003, Combinatorial chemistry & high throughput screening.

[61]  Pete Moore,et al.  To affinity and beyond , 2003, Nature.

[62]  F. Salemme,et al.  Chemical genomics as an emerging paradigm for postgenomic drug discovery. , 2003, Pharmacogenomics.

[63]  S. Schreiber.  PERSPECTIVE: THE SMALL-MOLECULE APPROACH TO BIOLOGYChemical genetics and diversity-oriented organic synthesis make possible the systematic exploration of biology , 2003 .

[64]  Bhupinder Bhullar,et al.  Self-Assembling Protein Microarrays , 2004, Science.

[65]  Terry Walsh,et al.  Countering cooperative effects in protease inhibitors using constrained beta-strand-mimicking templates in focused combinatorial libraries. , 2004, Journal of medicinal chemistry.

[66]  P. Arya,et al.  A solid phase library synthesis of hydroxyindoline-derived tricyclic derivatives by Mitsunobu approach. , 2004, Journal of combinatorial chemistry.

[67]  David E Root,et al.  A flexible data analysis tool for chemical genetic screens. , 2004, Chemistry & biology.

[68]  B. Stockwell,et al.  Indoprofen upregulates the survival motor neuron protein through a cyclooxygenase-independent mechanism. , 2004, Chemistry & biology.

[69]  Patrick Jimonet,et al.  Strategies for designing GPCR-focused libraries and screening sets. , 2004, Current opinion in drug discovery & development.

[70]  Hege S. Beard,et al.  Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. , 2004, Journal of medicinal chemistry.

[71]  T. Mitchison,et al.  A high-throughput cell migration assay using scratch wound healing, a comparison of image-based readout methods , 2004, BMC biotechnology.

[72]  Todd R Golub,et al.  Gene expression–based high-throughput screening(GE-HTS) and application to leukemia differentiation , 2004, Nature Genetics.

[73]  Tudor I. Oprea,et al.  Pursuing the leadlikeness concept in pharmaceutical research. , 2004, Current opinion in chemical biology.

[74]  S Stanley Young,et al.  Design of diversity and focused combinatorial libraries in drug discovery. , 2004, Current opinion in drug discovery & development.

[75]  Stuart L Schreiber,et al.  A planning strategy for diversity-oriented synthesis. , 2004, Angewandte Chemie.

[76]  A. Tobin,et al.  A cell-based screen for drugs to treat Huntington's disease , 2004, Neurobiology of Disease.

[77]  V. Cornish,et al.  Finding Cinderella after the ball: a three-hybrid approach to drug target identification. , 2004, Chemistry & biology.

[78]  A solid-phase, library synthesis of natural-product-like derivatives from an enantiomerically pure tetrahydroquinoline scaffold. , 2004, Journal of combinatorial chemistry.

[79]  Tudor I. Oprea,et al.  Integrating virtual screening in lead discovery. , 2004, Current opinion in chemical biology.