INDEX

Ab initio methods, 139Abiotic pathways, 117, 190, 195, 197, 202, 209ABT-737, 134Acetylation, 201Acquired immunodeficiency syndrome (AIDS),

4, 150, 160Actin, 170–173, 175, 178–183, 185, 242, 257,

270Actin-myosin interaction regulators, 182Acute promyelocytic leukemia (APL), 150Acylation, 200Adenoviruses, 198, 204ADF/cofilin family, 171Adult respiratory distress syndrome, 176Adverse reactions, 39Affinity beads:

biological and medical applications, 44, 49–55biological background, 39–40FG, 46, 55FGNE, 46latex, 40, 44, 50, 56medical applications, 49–56SG, 40–41, 46–55

Affinity chromatography, 14, 22–24, 40, 56, 82Affinity matrices, 7Affinity purification:

DNA-binding proteins using SG beads, 46–48magnetic nanocarriers for, 44–46

Protein Targeting with Small Molecules: Chemical Biology Techniques and Applications,Edited by Hiroyuki OsadaCopyright © 2009 John Wiley & Sons, Inc.

Agarose beads, 40, 48–49Agonist, defined, 123Alcohol capture strategy, 72Alcohols, 60, 66Aldehydes, 60–61Alkanethiolates, 63Alkoxyamine, 61–62Alkynes, 63, 197–198Alleles, deletion, 224, 227. See also Deletions;

Mutationsall-trans-retinoic acid (ATRA:1). See RAR

ligandsα-Actinin, 171, 180α-Glucosidase inhibitors, 161, 163–164Alverine citrate, 228Alzheimer’s disease (AD), 30, 142AMD10, 73–74Amidation, 53Amines, 60–62, 66Amino acids, 34, 132, 138, 189–190Aminocoumarin, 74Aminopeptidase inhibitors, 162–163Aminopeptidase N (APN), 87Ampicillin, 85Analogs:

replacement of natural with nonnatural,194–196

toolkit for glycosylation, 193–194

277

278 INDEX

ANDBA, 96–98Androgens, 150, 153, 155, 158, 162, 164Angiogenesis, 249Animal models, 58Annexin, 108, 275Antagonist, defined, 123Anthracene, 96Anti-angiogenic agents, 161–162Anti-inflammatory agents, 50, 176–177Antibiotics:

resistance to, 116screening of, 4therapies, 149, 209

Antibodies, 6, 41, 69, 71–72, 204Anticancer agents, 50API497, 83AR antagonists, 152–155araC, 54–55Arf1, 184ARHGEF6, 180ARNO, 184Arp2/3, 170–171, 173, 178Arylboronic acids, 96–98Aspergillus:

alliaceus, 125fumigatus, 248

Aspirin, 199ATP, 105, 117, 135, 183ATRA therapy, 150–151Attachment chemistry, 60A2B5, 206Austin Method 1 (AM1), 32AutoDock/AutoDock Tools, 33, 139Automated flash chromatography, 127Azides, 63, 197–198, 209–210

Bacillus laterosporus, 267Bacteria, 41, 125, 173, 204–205, 209BAD protein, 6BALL-1 cells, 244Barcode, defined, 22Barcode-based chemical genetic profiling, 229Batch-throughput solid-phase extraction, 127B cells, 258Bcl-2, 134Bcl-XL protein, 6Beauveria felina, 252Benomyl, 229Benzimidazolium, 104Benzoic acid, 151Benzoquinonoid ansamycins, 250β-catenin, 207β-Lactamase, 83β-secretase (BACE-1), 142

β2 integrins, 179–180BIAcore evaluation software, 88BIM1 gene, 229Binding affinity, 39, 85–87, 133, 157–158Binding proteins, 40, 48, 50–53, 60Biodegradables, 69, 71Biological response modifiers (BRMs):

classification of, 149–150defined, 149NR antagonists, 152–156, 165nuclear receptor ligands, 156–160RAR ligands, 150–152, 165structural development studies, 165thalidomide-related molecules, 160–165

Biopanning, 82–85, 87–88Biopolymeric materials, 207Bioprobes:

applications, generally, 2defined, 1development of, 4

Bioscreening, 41Biotin, 68, 207, 210Biotin-YZZZ, 83Biotinylation, 66, 82, 240, 243, 249, 257–259,

263–264, 270, 275BK virus, 204–205BLAST, 86Boltzmann constant, 119Boronic acid derivatives, 95–98Bovine carbonic anhydrase II (CA), 74Boyden chamber assay, 174BRCT, 136Breakthrough volume, 133BRENDA, 117Burkitt’s lymphoma, 54Butanoylation, 200Butyrate groups, 200–201

Cachexia, 160–161Calcineurin, 247Calcium level, 172Calmodulin (CaM), 73–74, 86–88Calmoduphilin, 73Calpain, 172Cancer/cancer cells, see specific types of cancer

characteristics of, 173, 177, 184, 185,201–204, 210–211

metastases, 177, 184, 202therapies, 127, 202–204

Capsid proteins, 82–83Carbohydrate(s)

microarray analysis, 59, 63, 67–68, 70sensing, 95–96, 98–99

INDEX 279

Carbohydrate–carbohydrate interactions, 196,206

Carboxylic acids, 60, 66Caspase inhibitors, 74–75Catalytic poisons, 121Ca2+/calmodulin (Ca2+/CaM), 82, 87–88, 173,

180, 183Cavbase, 141CCR3 receptor, 176–177Cdc42, 170–173, 177–179CD4+ T-cells, 4cDNAs, 82, 84–86, 88–89, 224, 242, 269Cell adhesion, 162, 179, 182, 196, 198, 206–208Cell blebbing, 183Cell–cell interactions, 170, 195, 207Cell cycle, 5, 87, 201, 225, 231, 233, 244, 267,

269Cell differentiation, 206–208, 266, 273Cell growth inhibitors, 5Cell migration:

cell polarization, 170, 173inhibitors, see Cell migration inhibitorsunderlying molecular mechanisms, 170

Cell migration inhibitors, molecular mechanismsof:

extracellular stimuli, 170, 173, 175intracellular molecular networks, 177

CELLProfiler, 174Cell signaling, 195, 204Cell spreading, 183Cell surface oligosaccharides:

glycosylation process, 193–201metabolic oligosaccharide engineering (MOE),

190Cell–substrate interactions, 170Cellular retinoic acid-binding protein (CRABP),

151Cellular uptake, 193, 198–199, 200, 202Cerulenin, 245Chembridge EXPRESS-Pick database, 143Chemical arrays, see Small-molecule microarrays

defined, 58fabrication strategies, 59–70historical perspectives, 57–58inhibitor discovery, 72–75key technological elements, 59ligand discovery, 72–75signal detection methods, 70–72

Chemical biology:of cell motility inhibitors, 169–186defined, 1bioprobe applications, 2chemical genomics distinguished from, 3trends in, 8

Chemical chips, 58Chemical genetics:

classical genetics distinguished from, 2, 57–58ligand and inhibitor discovery, chemical array

applications, 59, 72–75Chemical genomics:

defined, 226overview of, 223–224postgenomic era, 224yeast model, see Yeast genetics

Chemokine family, 175Chemoselective ligation strategy 197–198, 210Chenodeoxycholic acid (CDCA), 158–159Chirality, 129Chlamydocin, 272Chlorophosphates, 95Cholecystokinin antagonists, 125Cholesterol synthesis pathway, 179Chromeceptin, 239–240“Click” chemistry, 94, 210“Click” ligation, 197Cloning, 231CNB1 gene, 229Colon cancer, 83, 87, 150Combinatorial chemistry (combichem), 3, 40, 56,

105, 124–125, 127–130Compactin, 226COMPARE analysis, 260Competitive antagonists, 123Competitive inhibitors, 52, 121–122Compound–gene interaction, 229, 234Computational analysis, 229Computer-assisted docking (CAD) studies,

151–157Concanavalin A (Con A), 98–99Conformational analysis, 137, 152, 154–155Consensus sequence, 47–48Copper, 103Coprecipitation, 41Coronavirus, 204Cortactin, 171Coulombic interaction, 139Covalent capture strategy, 65–66Covalent immobilization:

site-nonspecific, 63–66site-specific, 59–63

Covalent modifications, 121Creatine kinase inhibitors, 134Crm1, 231–233Crude plant extracts, 125Cryogenic technologies, 134CTLL-2, 255–256CuQAMF, 103Curcumin, 87

280 INDEX

Cy3, 74Cy5, 72–73Cyclic adenosine 3′,5′-monophosphate (cAMP),

106Cyclic guanosine 3′,5′-monophosphate (cGMP),

106–107Cycloadditions, chemical array fabrication,

62–63Cyclophilin, 3Cyclosporine, 3Cyclosporine A, 3, 229Cylindrol, 185Cysteine, 62, 245, 257, 259Cytidine monophosphate (CMP), 193–194, 200,

202Cytochalasins, 181Cytokines, 5, 160Cytomegalovirus, 204Cytosol, 50, 203Cytotoxicity, 54–55

Dansylamide, 74Databases:

BRENDA, 117Chembridge EXPRESS-Pick, 143small-molecule interaction (SMID), 33

Data mining, 174dCK enzyme, 54DCP-S4, 95Deamination, 190Deletion mutants, 224–234Density functional theory, 1391-Deoxynojirimycin (dNM), 16415-Deoxyspergualin (DSG), 267–268Depolymerization, 242, 257Dereplication, 125Dermatological diseases, 150Dexamethasone, 19Diabetes, 98–99, 159–160, 163, 2101,2-Diaminofluoresceins (DAFs), 102–103Diffusion, 1201,25-Dihydroxyvitamin D3 (DHD3), 155–156Diminutol, 241–242Dipeptidyl peptidase IV (DPP-IV), 162, 1643,3-Diphenylpentane, 156–160, 165Directed cell migration, 169Discodermolide, 126–127Diversity-directed sensors, 103–105Diversity-oriented library, 124Diversity-oriented synthesis (DOS), 60, 72Divinylbenzene (DVB), 41, 45DMAG-N-oxide, 184DNA:

alkylation, 182

ligase, 47microarray, 59, 70, 227, 229, 239oligomers, 47–48polymerases, 244sequence, 88, 190, 227synthesis, 242topoisomerase, 244, 264

DNA–DNA interactions, 70DNA–RNA interactions, 70DNA–SM interactions, 25Docking, 86–88, 138, 140, 142–143, 151Dose-response data, 58Dosing, whole-organism, 200Down-regulation, 196, 268Doxorubicin, 83, 203DPHK-01, 159–160Drug design, 40, 123Drug development, 3–4, 24, 40Drug discovery, 56, 103, 105, 123–124, 129,

190. See also New drug(s)Drug–drug interactions, 31Drug-induced haploinsufficiency, 14, 227Drug sensitivity tests, 227Drug target screening, 40Duplication, 225Dyclonine, 224, 228Dyes, types of, 93Dynamic laser scattering (DLS) analysis, 45Dyslipidemia, 159

EC-17 cells, 185–186Efficacy studies, 39. 48–49Ehrlich, Paul, 123EHT1864, 178Electrochemical impedance spectroscopy (EIS),

26–27Electrochemical interaction detection, 25–27Electrons:

density, 133, 139transfer reactions, 121

Electrospray ionization (ESI), 132Electrostatic forces, 136–137Eluted phage, small molecule identification, 85Encapsulation, magnetite nanoparticles, 42Encoded self-assembling chemical (ESAC):

DNA-, 68library, 66–67, 71, 74PNA-, 67, 71

Endothelial protein C receptor (EPCR), 83Endothermic processes, 135Energy profile, 117–119, 121Entamoeba, 204ent-15-oxokaurenoic acid (EKA), 242–243Enthalpy, 120, 135–136

INDEX 281

Entropy, 120, 135–136Enzyme catalysis theory, 117–121Enzyme inhibitors, see Inhibitors

commercial applications, 116–117derived from thalidomide, 162–165theoretical background, 121–122types of, 121

Enzyme-linked immunosorbent assay (ELISA),14, 69, 173, 180

Enzyme–SM interactions, 116–117Epitopes, 195, 196, 198, 202, 204, 210, 233, 247Epolactaene, 244–245Equilibrium geometry, 137ERG7 gene, 227ERG11 gene, 229ERK, 170, 172, 180, 185, 266–267Escherichia coli, 82–85, 107, 135, 183ES/mES cells, 265–266Esophageal cancer, 185E3330, 49–50Ethylene glycol diglycidyl ether (EGDE), 46Eukaryotes, 18, 173, 209, 224–225Exothermic processes, 135Extracellular matrix (ECM), 170, 172, 179, 196

F-actin, 181–182FAK, 170, 172, 180Farnesyl pyrophosphate, 179Farnesyl transferase (FTase), 170, 184–185FE-TEM, 46Fenofibrate, 159Fenproprimorph, 228Fermentation, 4, 125FG beads, 46, 55FGNE beads, 46Fibroblast growth factor 10 (FGF-10), 162Fibronectin, 180Fick’s law, 120Field-effect transistors, 26Filopodia, 170–171Fission yeast, 225, 231–233, 270FK506, 3, 19, 48–49, 83, 246–247FK506-binding protein (FKBP), 3, 134, 226, 247FKBP12, 48FLAG:

epitopes, 210, 233peptide, 198

FlCRhR, 106FlexX software, 88, 143FLIPE, 107Fluconazole, 229Fluoresceins, 93, 100, 194Fluorescence, 50, 91Fluorescent lifetime (FLIM), 105

Fluorescent probes for small molecules:genetically encoded probes, 105–108probe design, 93–95probes based on small molecules, 95–103sensing fluorophores, 103–105

Fluorescent protein (FP), 18Fluorescent resonant energy transfer (FRET), 14,

71, 91–92, 98, 105–108Fluorophore–fluorophore interaction, 106Fluorophores, 91–96, 99, 103–105Fmoc/tBu chemistry, 69Focused library, 124, 129–130Folate, 54Forward-affinity binding assay, 86–87Forward genetics:

chemical, 175, 177, 180, 183defined, 224

4,7FPP-33, 165Fragile binding, 59Fragment libraries, 130–131FRAP-1, 243Free energy, 118, 136–137FRET sensors, 98, 106–107FR901464, 269–270Frontal affinity chromatography-mass

spectrometry (FAC-MS), 23–24, 132–133Front-membrane protrusion formation process,

1715-FU, 228Fumagillin, 4, 248–249Functional genomics, 234Functional groups:

chemical array fabrication, 60–63, 65–66, 68glycosylation process, 196–197ligand design, 137STD experiments, 134tissue engineering, 207

Fungicides, 117Fungus, 125Fusion proteins, 6, 18, 44, 106FXR ligands, 158–160

G-actin, 181γ-parvin, 179–180Gas chromatography-mass spectrometry

(GC-MS), 132–133GDH-lacZ, 72–73GEFs, 171–172, 177Geldanamycin, 250–251Gene deletions, 21–22, 224–230Gene-dosage effects, 225Gene–gene interaction, 229, 234Gene knockout technique, 3

282 INDEX

Generic library, 124Genetic engineering, 190Genetics:

chemical, see Chemical geneticsclassical, 57–58forward, 183, 224reverse, 224yeast, see Yeast genetics

Genome sequence, 224–227Genomic DNA, 54Geometry optimization, 137–141Geranylgeranyl pyrophosphate, 179Gerfelin, 5, 252–253GGTase, 185Gibbs free energy, 17, 32, 135–137, 139, 142Glass slides, chemical array fabrication studies,

60–62, 68–69Glucocorticoids, 19Glucose levels, 98Glutathione (GSH), 104Glutathione S-transferase (GST), 72Glycans:

diversity of, 193manipulation of, 190–193, 209metabolically engineered, cell surface

alterations, 196–198Glycocalyx, 190, 197, 204–207Glycoconjugates, 65Glycomics, 210–211Glycoproteins, 194, 197, 202, 205Glycosidation, 164Glycosoaminoglycans (GAGs), 191, 193–194Glycosphingolipids (GSLs), 196Glycosylation:

components of, 189–190MOE pathways, 192–193protein therapeutics, 208–209tissue engineering, 208

Glycosyl ligands, 69Glycosynapses, 196, 206GM3, 196, 201GMA, 40–41, 44–46GPAs, 171Graft-versus-host disease (GVHD), 150Green fluorescent protein (GFP), 94GROMACS, 33Ground-state wavefunction, 139g3p/g8p, 83–84GTPases, 170–172, 174, 177–179, 183–184GTP-binding protein-coupled receptors (GPCRs),

171GTP Green, 104–105Guanine nucleotide exchange factor (GEF), 177GW4064, 158

Hansen’s disease, 150Haploinsufficiency, 227–230Haptamide A, 72–73Haptamides, 72–73Hap3p, 72–73HBC (hydrazinobenzoicurcumin), 82–83, 86–87HCT116, 83Heat shock proteins (HSPs):

characteristics of, 268HSP60, 245HSP70, 268HSP90, 184, 251, 263–264

HeLa cell, 48, 52, 210, 261, 262Helicoma ambiens, 271Heme, 50, 52–53Hemin, 52Hemophilus ducryei, 205Hepatitis virus, 204HepG2 cells, 98, 107Hierarchical clustering analysis, 229High-affinity binding, 108High-content screening, 174High-performance liquid chromatography

(HPLC), 30, 127High-throughput quantitative technologies, 116High-throughput screening (HTS), 5, 13, 27–28,

59, 66, 69–70, 125–127, 129, 132–133,142–143, 174, 176, 227

Histidines, 30, 249HL-60 cells, 156–157, 207Homologous recombination, 226Homology modeling, 140–141Homology search, 86Hormone, 5Horseradish peroxidase (HRP), 2105HPP-33, 165H-ras, 185–186HS-Sultan cells, 54H12-folding inhibition hypothesis, 152–156, 165HT29, 83Human genome, 128, 150Human immunodeficiency virus (HIV), 4,

162–163, 204, 231Human papillomavirus E7 protein, 30Human polyoma virus, 204, 205Human serum albumin (HSA), 74Hydrazides, 203, 207Hydrogen bonds, 121, 132, 136–138, 157Hydrogen peroxide (H2O2), 93, 100–102, 107Hydrogen transfer reactions, 121Hydrolysis, 203Hydroquinone group, 63Hydroxamic acids, 66Hydroxyl group, 54, 157

INDEX 283

3-Hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase, 179

Hyperlipoproteinemia, 163Hypersensitivity, 227–228, 231Hypervitaminosis A, 151Hypoxia-inducible factor-1 (HIF-1), 124

IGF2, 239–240IgG ligands, 74ILK, 180ImageJ, 174Imaging studies, surface plasmon resonance

(SPR), 8, 71Immobilization:

covalent, site-specific/nonspecific, 60–66noncovalent, site-specific/nonspecific, 66–69small molecule, 57–80, 84–85

Immune cells, 41Immunization, 204Immunogenicity, 208Immunoglobulins, 74Immunophilin, 3Immunosuppressive agents, 3, 50, 48, 225, 247,

254, 258, 268, 275Immunosurveillance, 204Infectious agents, 204–206Infectious diseases, 149Influenza/influenza virus, 195, 204Inhibitors:

candidates, 125discovery and development of, 123–124, 142fragment-based design, 130–131irreversible, 121library-based approaches, 124–130rational design, 141, 143target selection, 124

Insect cells, MOE-based therapies, 208–209In situ hybridization, 70In situ synthesis, 59–60, 69–70Insulin, 190Integrated-circuit microcalorimeters, 136Integrins, 172, 174, 179–180, 184, 195–196,

200–201, 206–207Interferon therapy, 209Interleukin-2 (IL-2), 247Inverser agonist, 123Ionic bonds, 121Irreversible inhibitors, 121Isocyanate, 60, 65Isoprenoids, 179Isoquinoline, 183Isothermal titration calorimetry (ITC), 15, 123,

135–136, 143ISP-1, see Myriocin

JK273, 179–180Jurkat cell, 48–49

KD value, 66, 72–74Ketones, 197–198, 201, 203, 207Ketopantoate reductase (KPR), 135KGF, 173Kinase inhibitors, 173Kinetics:

association, 29, 31binding, 25dissociation, 29, 31fractal, 120Michaelis-Menten (MM), 117–120

Labeling, in signal detection, 70Lactacystin, 8, 244Lactobacilli plantarum, 205Lamellipodia, 170, 172, 177Lanthanide, 93Larmor frequency, 133Latex beads, 40, 44, 50Latrunculins, 181Lectins, 65LEHD-MCA, 75Leishmania, 204Lennard-Jones potential function, 136Leprosy, 150Leptomycin B (LMB), 231–233leu1, 233Leucovorin, 54Leukemia, 54–55, 244, 258, 265, 267Leukocytes, 169, 173, 175, 179–180Leukotrienes B4-2 hydroxydehydrogenase,

242Ligand(s):

chips, 58design of, see Ligand designdevelopment of, 123

Ligand binding:characteristics of, 41, 123, 196proteins, 7, 39sensors, 93

Ligand design:in silico principles, 136–137, 143rational, 142–143structure-based, 139–140target-based, 140–141tools of the trade, 137–139

Ligand–protein interactions, 8Ligand–receptor interactions, 122–123Linear interaction energy with continuum

electrostatics (LIECE), 142Lineweaver-Burk plot, 52, 118–119

284 INDEX

Lipinski’s rule of 5, 128Lipooligosaccharides, 205Liquid chromatography-evaporative

light-scattering detection-mass spectrometry(LC-ELSD-MS), 127

Liquid scintillation counter, 54Listeria, 173, 183LM11, 184Locostatin, 184–185Low-affinity binding, 59Low-molecular-weight fluorophores, 93Low-throughput analysis, 136Luciferase, 124Lymphoma, 54–55Lysine, 62

Macrophage colony-stimulating factor (M-CSF),5

Macrophages, 4, 95, 103, 106, 160, 183MAG, 195, 206Magnetic beads:

affinity latex beads, 40–41, 43, 45, 50glycomic studies, 210magnetic nanocarriers for affinity purification,

44–46size-controlled magnetite nanoparticles,

preparation of, 41–43Magnetic resonance imaging (MRI), 203Magnetic separation technology, 40–41, 210Magnetite nanoparticles (MNPs), 41–44Magnetite particles (MPs), 43–44Mammalian cell, 8, 181, 205ManNLev, 198–201, 203, 207Mannose-6-phosphate, 209ManNPh, 203ManNProp, 196, 200, 205–207Mass spectrometry (MS), 23, 132–133, 210,

243, 256Mass-to-charge (m/z) ratios, 132Matrix-assisted laser desorption ionization

(MALDI), 132Matrix-assisted laser desorption ionization-time

of flight (MALDI-TOF), 28Matrix-assisted laser desorption ionization-time

of flight mass spectrometry(MALDI-TOF-MS), 28, 30, 242

Maximal reaction velocity (Vmax ), 119MCF-7 cells, 98MDCK cell migration, 185–186Meiosis, 225Melanogenin, 253–254Melanoma cells, 185–186Metabolic disorders, 210Metabolic glycoengineering, 190

Metabolic oligosaccharide engineering (MOE):defined, 190glycan manipulation, 190–193glycosylation studies, 193–201goal of, 193therapies, 202–211unanticipated effects of, 200–201

Metal ion sensors, 92, 93–94Metalloporphyrin, 50Methionine aminpeptidase (MetAP2), 249Methotrexate (MTX), target protein

identification, 53–55Methylgerfelin, 5, 252–253Mg2+, 180Michaelis-Menten (MM) kinetics, 117–121Michael reaction, 60, 231Microarray analysis, 22. See also DNA,

microarray analysisMicrospots, 59Mitochondrial transporters, identification of,

50–53Mitosis, 6, 225, 241–242Mixed noncompetitive inhibitors, 122MLC kinase (MLCK), 170, 172, 182–183ML-7/ML-9, 182–183Modes of action, 233–234Molds, 125Molecular biology techniques, 2, 190Molecular mechanics force fields (MMFFs), 32,

139Molecular mechanisms of diseases, 57Molecular networks, intracellular, 177–186Molsidomine, 227–228Monosaccharides, 190, 193–194, 197, 200, 209Monosporuim bonorden, 262–263Moore’s law, 31Moverastin, 184–186mRNA, 196, 200, 210, 231, 244, 262, 270MTOC, 170–171mTOR, 134Multifunctional protein-2 (MFP-2), 240Multiple myeloma (MM), 8, 150Multiple sclerosis, 169Multitarget drug, 164Mutations, 224, 226–228Mycalolilde, 181Mycobacterial extracts, 56Myosin light-chain (MLC), 172, 182Myosin II, 172, 182Myriocin, 254–256

N-acetyl-D-galactosamine (GalNAc) analogs,193–194, 200

INDEX 285

N-acetyl-D-glucosamine (GlcNAc) analogs,193–194, 196, 200–201, 210

N-acetyl-D-mannosamine (ManNAc) analogs,193–195, 198, 200–203, 209

N-acetyl-D-neuraminic acid (Neu5Ac) analogs,193–195, 200, 202, 204, 205, 206, 209

NADP-dependent quinone oxidoreductase(NQO1), 242

NADPH, 135Nanobeads, 40–41, 50Nanolithography, 26, 30National Cancer Institute Diversity library, 143Natural Product Collaborative Drug Discovery

Group, 127Natural product libraries, 125, 127, 129–130,

143N-(2-Boronobenzl)-6-methoxyquinolinium

(o-BMOQBA), 97–99Nck protein, 171Near-infrared fluorescence imaging, 95Nef–SH3 interaction, 142–143Nerve agent mimics, 95Neuronal nitric oxide synthase (nNOS), 131Neutrophils, 176, 207New drug(s):

candidates, 125, 129, 131, 142development, 3–4

Newcastle disease virus, 204Nexavar, 129NF-κB, 5, 49, 252N-glycol-D-neuraminic acid (Neu5Gc) analogs,

193, 195, 202, 20615N-heteronuclear single-quantum correlation

(15N-HSQC), 134N-hydroxysuccinimide (NHS) ester, 62Nitric oxide (NO), 92, 100–103Nitric oxide synthase (NOS) enzymes, 131Nitroveratryloxycarbony (NVOC), 63N-linked oligosaccharides, 195nmt1, 232–233Noncompetitive antagonists, 123Noncompetitive inhibitors, 122Noncovalent immobilization:

site-nonspecific, 68–69site-specific, 66–68

Novartis, 127NPIQ, 162Nuclear export signal (NES) sequence, 231–233Nuclear magnetic resonance (NMR), 127,

133–134, 143Nuclear Overhauser effect (NOE), 133Nuclear receptor (NR) ligands:

antagonists based on helix 12-foldinginhibition hypothesis, 152–156, 165

characteristics of, 149–152, 165with 3,3-diphenylpentane skeleton, 156–160,

165Nucleic acids, 41Nucleotide(s):

sequence, 83, 89synthesis, 70

Obesity, 163, 211Off-resonance spectra, 134O-GlcNac, 194, 197, 210–211Oligonucleotide(s):

arrays, 227functions of, 66–67microarray analysis, 22

Oligosaccharides, 60, 63, 190, 193, 197, 209. Seealso Cell surface oligosaccharides

On-resonance spectra, 134Open reading frames (ORFs), 224, 231–233Open-source image analysis packages, 174Organic synthesis, 127Orthologs, 225Osteoclastogenesis, 5, 252Osteoporosis, 5, 169Oxidative stress, 99, 1012-Oxoglutarate carrier (OGC), 52–53OxyR, 101, 107

Paget’s disease, 156Pain management, 115PAK1, 170–171, 177Palau’amine, 83Palladium meso-tetra(4-aminophenyl)porphyrin

(PdTAPP), 50–52Palladium meso-tetra(4-carboxyphenyl porphyrin)

(PdTCPP), 50–52Pandemics, global, 204Paper disk agar plate method, 4Papovavirus, 204Papuamide B, 230Parallel synthesis, 69Parasites, protozoan, 204–205Partitioning, 192, 200Paxillin, 170, 172, 1801-(p-Boronophenyl)-4-(p-dimethylaminophenyl)

buta-1,3-diene (DDPBBA), 97–98PC12 cells, 107Peptide bonds, 189–191Peptide nucleic acids (PNAs), 66–67Peptides:

glycosylation process, 189microarray analysis, 59, 61, 63microsequencing, 240synthetic, 89

286 INDEX

Pesticides, 33–34, 116–117Pg-ompA1, 83PG1, 100–101Phage display technique, target protein

identification:characteristics of, 82–84of HBC, 87small molecules, 84–87validation, 85–89

Phalloidin, 181Pharmacophores, 66–67, 125, 131, 142,

160, 164Phenols, 60, 66Phenotypic analyses, 5, 174, 226Phoslactomycin A, 256–257Phosphatidylcholine (PC) synthesis, 268Phosphoinositides, 171Phospholipids, 108, 172Phosphorylation, 54, 172, 182, 185Photochemistry, 70Photo-deprotection chemistry, 70Photo-induced electron transfer (PET), 95–96Photolithography, 26, 70Phylogenetic analysis, 225Physicochemical analysis, 4Physicochemical properties, 4Pironetin, 258–260Pivaloyl group, 157–158Pladienolide, 260–262Planck’s constant, 119Plasmodia, 204Platelet-derived endothelial cell growth factor

(PD-ECGF), 161–162Pleckstrin homology (PH), 105, 108Pluripotin. See SC1Pocketome, defined, 32Poisson-Boltzmann equation, 138Polarization, 126–127, 136, 170–171, 173, 176Polo-box domin (PBD), 5–6Polo-like kinase 1 (Plk1), 5–6Polyamidoamine (PAMAM) dendrimers, 63–64Poly-(D), (L)-lactide/glycolide (PLGA), 69, 71Polyethylene, 69Polymerase chain reaction (PCR), 22, 67,

226–227, 231Polymerization, 44–46, 170–174, 178, 180–183,

185, 241–242, 257, 259Polymer nanobeads, 40Polymers, 62, 69, 71Polyoma virus, 204Polypeptides, 84Polysaccharides, 190, 209Polystyrene (poly-St)/polyglycidyl methacrylate

(poly-GMA), 40

Polystyrene beads, 128Porphyrins, 50–53Post-translational modifications (PTMs), 18–19,

172, 179, 189–191, 208, 211Potential energy, 117–118, 136–137, 139PPAR ligands, 158–160Prenylation, 179, 185Primers, 22Probes:

based on small molecules, 95–103design of, 93–95genetically encoded, 105–108

Prodrugs, 199–200Profilin, 171Profiling, 6–7, 223, 227–230Prokaryotes, 28Proof-of-principle studies, 227Prostate cancer/tumors, 150, 152, 154, 162Proteases, 62, 71Proteasomes, 8Protein(s):

analysis strategies, 190diversity, 189–190DNA-binding, 46–48docking modeling, 86–87fluorescent, 93–94, 105–107folding, 190lipid-binding, 108microarray analysis, 59, 61, 63, 82, 124oncogenic, 251printing methods, 30recombinant, 208–209resonance, 134small-molecule modulators, 46–48, 58–59structure, 195therapeutics, 208, 210

Protein-binding assays, 66, 70–71, 75Protein Data Bank, 142Protein kinase A (PKA), 106–107Protein kinase C (PKC), 105, 108, 171–172Protein-ligand:

binding, 135interactions, 31, 62, 133screening, 72

Protein/ligand molar ratio, 135Protein-nucleic acid interaction, 116, 134Protein-protein interactions, 5–6, 18, 25, 27,

116, 127, 129, 134–136, 142, 180Protein-SM interactions, 25, 116, 137Proteome library, binding to small molecule,

85Proteome-scale interaction maps, 18Proteomic analysis, 210, 225Pseudomonas spp., 269

INDEX 287

p60src , 250PTEN, 170–171p21 gene, 201Public health policies, 57Puromycin-sensitive aminopeptidase (PSA),

162–164Purpurogallin (PPG), 6PUT1-lacZ, 72Pyrene excimer fluorescence, 173Pyridine, 1833-(4-Pyridyl)indole, 183

Q-TOF MS analysis, 49, 54Quality control, 129Quantitative structure-activity relationship

(QSAR), 137, 139–140Quantum dots (QDs), 94, 198Quantum physics, 121Quantum tunneling, 121Quartz crystal microbalance (QCM), 24–25, 27Quenching, 94–96Quinocaumycin, 182Quinone, 49

Rabies virus, 204Rac/Rac1, 171, 177–178Radicicol, 262–264Radio-frequency radiation, 133Radixin, 181–182Raf kinase inhibitor protein (RKIP), 184–185RanBP2, 243Rapamycin, 225–226, 247RAP�id-4 system, 25Rap1, 172RAR ligands, 150–152, 165Ratiometric analysis, 105Rational drug design, 136, 140Reactive oxygen species (ROS), 99–101Receptor blockers, 116Receptor-ligand interaction screening, 123Recombinant technology, 208–209, 225Recombinant therapeutics, 209Reflectometric interference spectroscopy (RIFS),

28Refractive index, 28, 71Regenerative medicine, 206–208Reovirus, 204Research Collaboratory for Structural

Bioinformatics (RCSB), 140–142Resorufin (PR1), 100–101Respiratory diseases:

asthma, 176, 180bronchitis, chronic, 176

Retinoblastoma, 30

Retinoids. See RAR ligandsRetinoid X receptor (RXR), 150–153Reverse-affinity binding assay, 86–87Reverse chemical proteomics, 84Reverse genetics, 224Reversible inhibitors, 121Rheumatoid arthritis, 5, 50, 150Rhinovirus, 204Rho family, 170–171, 174, 177–179, 183Rho kinase (ROCK)/ROCK inhibitor, 172,

182–183Ribosomal RNA (rRNA), 228Ricin, 203Rigidity, 129RNA, see mRNA; RNAi; siRNA

polymerase, 18RNAi, 175Rotavirus, 204

Saccharomyces:cerevisiae, 4, 18, 173, 183, 224–226, 231, 234pombe, 225, 231–234

Salvarsan, 123SAR by NMR, 133–134Saturation transfer difference spectroscopy

(STD), 134SB225002, 176SC-3 cells, 158SC1, 265–267Scintillation proximity assay (SPA), 15Sclerosis, 169, 180SDS-PAGE, 48–52, 54SDS-polyacrylamide gel, 52Secondary tests, 125Secramine A, 178Seed polymerization, 40, 45Self-aggregation, 44Sensors, types of, 91–92SG beads, 40–41, 46–55SGNE-COOH beads, 53SGNEGDE beads, 48SH-SY5Y, 244Shikonin, 177Short-chain fatty acids (SCFAs), 199–201, 203,

210Sia5Lev, 198, 200Sialic acid, 193–196, 198, 200–206, 209Sialidases, 196, 205–206, 210Sialoside, 204–205, 209Signal detection:

methods of, 59in miscellaneous assays, 71–72in protein-binding assay, 70–71

Signal transduction, 116, 170, 178, 179

288 INDEX

Silver staining, 47, 54SIN-1, 228Single-stranded DNA, 47, 82Single-walled carbon nanotubes (SWNTs), 26,

94–95, 99Site-directed mutagenesis, 135SM interaction predictions:

energy-based, 32–33sequence-based, 33–34

SM interaction screens:common technologies, 14–15quantitative label-free interaction profiling

systems, 22–31yeast-based genetic, 21–22yeast two-hybrid system, 18–21

SM ligand development:inhibitor discovery, design, and development,

123–135rational ligand design, 116, 136–143theoretical background, 116–123traditional, 116

Small interfering RNA (siRNA), 2–3, 87, 124,240, 243, 253

Small-molecule interaction database (SMID),33–34

Small molecule-protein interaction:chemical arrays, 59, 70chemical biology based on, 1–8

Small molecules (SMs):applications, generally, 304basics of, 11–13bifunctional, 65binding protein identification challenges,

46–49computational approaches to interaction

profiling, 31–34experimental approaches to interaction

profiling, 18–31interaction predictions, see SM interaction

predictionsinteraction screens, see SM interaction

screensinterventions, generally, 115–116ligand development, see SM ligand

developmentmicroarrays, 58-protein binding, 34screening systems, 4–6-SM interaction detection, 12target identification, 174–175theoretical background, 13, 16–19

SMID-BLAST tool, 34SMILES, 34SOCS-3, 240

Sodium dodecyl benzene sulfonate, 45Sodium dodecyl sulfate (SDS), 45Sparse matrix factorization analysis, 229Spergualin, 267–268Spliceostatin A, 269–270Split-and-pool synthesis, 60, 69, 128SPOT synthesis, 69–70Src family, 171, 180Staphylococcus aureus, 248STAT6, 239–240Statins, 179Statistical analysis, 139–140, 227Staudinger ligation strategy, 63Stem cell biology, 206–208Stenotrophomonas maltophilia, 83Steroid hormone:

androgen, 162receptors, 150

Steroids, 150, 158, 160, 162, 165Sterol biosynthesis, 227–228Stimuli, extracellular, 173, 175–177Streptomyces spp.:

hygroscopicus, 250isolated from, 8platensis, 260–261tsukubaensis, 247

Strong-affinity protein-expressing page, 85Structure-activity relationship (SAR):

by NMR, 133–134studies, 8, 56, 73, 125, 129, 210, 242,

244–245, 253, 270, 275Sugars:

characteristics of, 200–202MOE applications, 190–191, 193, 195,

206–211sensors, 96–98

Sulfonilamides, 129Sulfonylureas, 129Surface plasmon resonance (SPR) imaging,

8, 15, 17, 24, 27–31, 34, 49, 71–73,86–87

Surfactants, magnetic nanocarriers, 44–45Synthetic genetic array (SGA) analysis, 14,

228–229Synthetic lethality, 227–231Synthetic libraries, 127–130

TAC-101, 165Tacrolimus. See FK506Tagging strategies, 60Tannins, 127Target geometry, 137–138Target-ligand interaction, 137–139Target-oriented library, 124, 130

INDEX 289

Target proteins:identification using phage display technique,

81–89small molecule data, see specific molecular

targetsTaxol, 125, 127T cells, 4, 160, 162, 247, 255, 258, 273Tetrahydrofolate, 54Thalidomide:

α-glucosidase inhibitors derived from,163–164

aminopeptidase inhibitors derived from,162–163

anti-angiogenic agents derived from,161–162

characteristics of, 150enzyme inhibitors derived from, 162–165TNF-αproduction regulators derived from,

160–161, 163Thermodynamics, 17, 117–118, 120, 122, 135,

142Thermogravimetry (TG), 46Thiols, 60, 62, 66, 94, 190, 197–198,

207Thymidine phosphorylase (TP), 161–162Tissue engineering, 206–208TNF-α production regulators, 160–161, 163Toxicity, 149, 151, 200, 210–211Transcription factors, 18, 48, 55, 72, 151,

174Translocating sensors, 107–108Transmission electron microscopy (TEM), 42–43Trapoxin B, 271–273Trichomonas, 204Trifluoromethylaryldiazirine, 7Trypanosoma spp., 204–205T7 phage, 82–84TTP, 105Tuberculosis, 149TUB2 gene, 229Tubulin, 242, 259, 270, 273Tumor necrosis factor. See TNF-αTumors, 150–151, 153, 160, 162, 169, 202–203Tunicamycin, 226–227TWS119, 273–274Type I/II sensors, 91–93Type 2 diabetes, 159. See also DiabetesTyrosine, 172–179

U Dock 1.1, 138Ultraviolet irradiation, 7, 65Uncompetitive antagonists, 123Uncompetitive inhibitors, 121–122

U.S. Food and Drug Administration (FDA), 125,129, 150

Up-regulation, 54, 201, 253Ure2p, 72Uretupamines, 72–73UTP, 105

van der Waals, 32, 121, 136, 142Vascular disease, 169, 211VCAM-1, 180VDR:

antagonists, 155–156ligands, 156–157

VEGF, 173, 260Velcade, 8Vinblastine, 258–259Viral life cycle, 204Viral protein R (Vpr), 4Viruses, 41. See also Viral life cycle; specific

types of virusesVitamin A deficiency, 150VSM, 42, 44

WAVE/WASP proteins, 171, 177Western blotting analysis, 70Whole-genome transcription profiling analysis,

72–73WIP protein, 171Wiskostatin, 178–179Withaferin A (WA), 274–276Withania somnifera, 274– 275

Xenobiotic metabolism, 116Xenograft models, 261Xenopus spp., 173, 178, 241–242X-ray crystallography, 116, 131, 140, 249,

251–252X-ray crystal structure analysis, 152, 271X-ray diffraction, 42

Yeast genetics:budding yeast, 225–231chemical genomics, 224–225fission yeast, 225, 231–233, 270

Yeast-mammalian two-hybrid system, 20Yeast protein (Ure2p), 72Yeast two-hybrid:

system, 18–21technology, 15

Yellow fluorescent protein (YFP), 232–233

Zicao, 177