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Results for “Small Molecule Libraries”

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At least 307 records · Page 17Linked to original sources
PubMed2002

Profiling novel sulfonamide antitumor agents with cell-based phenotypic screens and array-based gene expression analysis.

A series of small molecules from sulfonamide-focused libraries have been evaluated in these laboratories to discover novel antitumor agents. Cell-based screens using flow cytometric analysis revealed the presence of two distinct classes of cell cycle inhibitors in this series; one (including E7010 and ER-67865) arrested mitosis by preventing tubulin polymerization; and the other (including E7070 and ER-68487) caused a decrease in the S-phase fraction along with cell cycle perturbation in G1 and/or G2 via an unknown mechanism(s). To further characterize both classes of antitumor sulfonamides with respect to their effects on gene expression, we used oligonucleotide microarray analysis for representative compounds. Consistent with the phenotypic observations, essentially the same transcription profiles were found between E7010 and ER-67865 and also between E7070 and ER-68487. However, there was very little overlap between genes affected by E7010 and E7070. As a characteristic expression change for microtubule-depolymerizing agents, the down-regulation of alpha-tubulin transcripts was evident in both E7010- and ER-67865-treated cells. On the other hand, E7070 and ER-68487 repressed significantly the expression of a variety of genes involved in metabolic processes, cell cycle progression, immune response, and signal transduction. Of the compounds examined, E7010 and E7070 have progressed to clinical trials, demonstrating some objective responses in the Phase I setting. Described herein is profiling of novel anticancer drug candidates from the sulfonamide class based on phenotypic screens and gene expression analysis. This includes a translational research that may suggest potentially useful markers for pharmacodynamic drug assessment in clinic.

Antineoplastic Agents↗
PubMed2004

Small-molecule dimerization inhibitors of wild-type and mutant HIV protease: a focused library approach.

We demonstrate that a focused library based on truncated, cross-linked interfacial peptides of HIV-1 protease produces effective dimerization inhibitors of the enzyme. By combining individual changes of the library into a single compound, we obtained a significantly more potent agent and found that an additive increase in inhibitor efficacy was obtained. The good activity of library members against an active-site drug-resistant protease mutant bodes well for dimerization inhibition as a complementary method to targeting the active site.

Binding Sites↗
PubMed2000

Designing small-molecule switches for protein-protein interactions.

Mutations introduced into human growth hormone (hGH) (Thr175 --> Gly-hGH) and the extracellular domain of the hGH receptor (Trp104 --> Gly-hGHbp) created a cavity at the protein-protein interface that resulted in binding affinity being reduced by a factor of 10(6). A small library of indole analogs was screened for small molecules that bind the cavity created by the mutations and restore binding affinity. The ligand 5-chloro-2-trichloromethylimidazole was found to increase the affinity of the mutant hormone for its receptor more than 1000-fold. Cell proliferation and JAK2 phosphorylation assays showed that the mutant hGH activates growth hormone signaling in the presence of added ligand. This approach may allow other protein-protein and protein-nucleic acid interactions to be switched on or off by the addition or depletion of exogenous small molecules.

Amino Acid Sequence↗
PubMed1999

Oligonucleotide aptamers that recognize small molecules.

Nucleic acid receptors ('aptamers'), which recognize a large variety of organic molecules of low molecular weight, have been isolated from combinatorial nucleic acid libraries by in vitro selection methods. Structural studies of nucleic acid-small molecule complexes provide insight into both the principles of molecular recognition by this class of biopolymers and the architecture of tertiary motifs in nucleic acid folding. Aptamers that recognize small molecules are increasingly applied as tools in molecular biology, from the detection of oxidative damage in DNA to conditional gene expression and from their use as modules for the engineering of allosteric ribozymes to biosensors.

Amino Acids↗
PubMed2006

Structure-based development of target-specific compound libraries.

The success or failure of a small-molecule drug discovery project ultimately lies in the choice of the scaffolds to be screened -- chosen from among the many millions of available compounds. Therefore, the methods used to design compound screening libraries are key for the development of new drugs that target a wide range of diseases. Currently, there is a trend towards the construction of receptor-structure-based focused libraries. Recent advances in high-throughput computational docking, NMR and crystallography have facilitated the development of these libraries. A structure-based target-specific library can save time and money by reducing the number of compounds to be experimentally tested, also improving the drug discovery success rate by identifying more-potent and specific binders.

Binding Sites↗
PubMed2002

Synthetic hosts by monomolecular imprinting inside dendrimers.

Synthetic host systems capable of selectively binding guest molecules are of interest for applications ranging from separations and chemical or biological sensing to the development of biomedical materials. Such host systems can be efficiently prepared by 'imprinting' polymers or inorganic materials with template molecules, which, upon removal, leave behind spatially arranged functional groups that act as recognition sites. However, molecularly imprinted polymers have limitations, including incomplete template removal, broad guest affinities and selectivities, and slow mass transfer. An alternative strategy for moulding desired recognition sites uses combinatorial libraries of assemblies that are made of a relatively small number of molecules, interconverting in dynamic equilibrium; upon addition of a target molecule, the library equilibrium shifts towards the best hosts. Here we describe the dynamic imprinting of dendritic macromolecules with porphyrin templates to yield synthetic host molecules containing one binding site each. The process is based on our general strategy to prepare cored dendrimers, and involves covalent attachment of dendrons to a porphyrin core, cross-linking of the end-groups of the dendrons, and removal of the porphyrin template by hydrolysis. In contrast to more traditional polymer imprinting, our approach ensures nearly homogeneous binding sites and quantitative template removal. Moreover, the hosts are soluble in common organic solvents and amenable to the incorporation of other functional groups, which should facilitate further development of this system for novel applications.

Benzene↗
PubMed2005

Web enabling technology for the design, enumeration, optimization and tracking of compound libraries.

Motivated by the need to augment Merck's in-house small molecule collection, web-based tools for designing, enumerating, optimizing and tracking compound libraries have been developed. The path leading to the current version of this Virtual Library Tool Kit (VLTK) is discussed in context of the (then) available commercial offerings and the constraints and requirements imposed by the end users. Though the effort was initiated to simplify the tasks of designing novel, drug-like and diverse compound libraries containing between 2K-10K unique entities, it has also evolved into a powerful tool for outsourcing syntheses as well as lead identification and optimization. The web tool includes components that select reagents, analyze synthons, identify backup reagents, enumerate libraries, calculate properties, optimize libraries and finally track the synthesized compounds through biological assays. In addition to accommodating project specific designs and virtual 3D library scanning, the application includes tools for parallel synthesis, laboratory automation and compound registration.

Combinatorial Chemistry Techniques↗
PubMed2006

How good is your screening library?

Efficient library design is an ongoing challenge for investigators seeking novel ligands for proteins, whether for drug discovery or chemical biology. Strategies that add neglected chemistry or exclude unproductive compounds are two dominant recent themes, as is a growing awareness of molecular complexity and its implications. The choice of how complex molecules in screening libraries should be often amounts to how big they should be. Small, simple molecules have lower affinities and must be screened at high concentration, but they will also have higher hit rates. Larger compounds, on the other hand, will often more closely resemble final drugs, but because they are more highly functionalized and specific, they will have much lower hit rates. The best general-purpose screening libraries may well be those of intermediate complexity that are free of artifact-causing nuisance compounds.

Combinatorial Chemistry Techniques↗
PubMed1998

Selection with SELEX Method of Small RNA Molecules Specifically Binding to Starch.

A 73-base DNA library with T7 promoter was chemically synthesized according to the sequence specified by the 2.5S RNA component of glycogen branching holoenzyme (EC 2.4.1.18) from rabbit muscle, in which 20 consecutive bases corresponding to a stem-loop structure were completely randomized. The in vitro transcribed RNA library was subjected to 9 successive rounds of selection with SELEX method, resulting in a sharp increase of the percentage of the starch-binding RNA from less than 0.01% for the first round pool to 31% for the ninth-round pool. This demonstrates the existence of small RNA species that can specifically bind to starch. Structural and functional analysis of them is in progress.

Journal Article↗
PubMed1997

Discovery of enzyme inhibitors through combinatorial chemistry.

This review serves to highlight the recent examples of combinatoric methodology as applied to the discovery and optimization of enzyme inhibitors. Early research efforts focused on the identification of polypeptides from libraries as inhibitors of proteases. As solution- and solid-phase chemistries gain in sophistication, libraries containing less peptidic structural motifs have been created. A recurring design stratagem relies on the synthesis of libraries incorporating pharmacophores with known affinity for the target enzyme. Screening of these structure-based libraries has led to the discovery of small-molecule inhibitors of both proteolytic and non-proteolytic enzymes alike. Two tables are provided listing the enzyme targeted libraries through 1996. A name, generic structure and size is given for each library citation, accompanied by the enzyme screen and the structure and potency of the most active library member.

Biotechnology↗
PubMed2002

A novel mitochondriotoxic small molecule that selectively inhibits tumor cell growth.

Tumorigenesis results from events that impinge on a variety of collaborating metabolic pathways. To assess their role in this process, we utilized a cell-based assay to perform a high-throughput, chemical library screen. In so doing, we identified F16, a small molecule that selectively inhibits proliferation of mammary epithelial, neu-overexpressing cells, as well as a variety of mouse mammary tumor and human breast cancer cell lines. F16 belongs to a group of structurally similar molecules with a delocalized positive charge. The compound is accumulated in mitochondria of responsive cells, driven by the membrane potential, and it compromises their functional integrity. Mitochondrial hyperpolarization is a shared feature of many tumor cell lines, explaining the broad action spectrum of this novel delocalized lipophilic cation.

Animals↗
PubMed2002

Erythropoietin mimetics derived from solution phase combinatorial libraries.

The erythropoietin receptor (EPOr) is activated by ligand-induced homodimerization, which leads to the proliferation and differentiation of erythroid progenitors. Through the screening of combinatorial libraries of dimeric iminodiacetic acid diamides, novel small molecule binders of EPOr were identified in a protein binding assay. Evaluation of a series of analogues led to optimization of binding subunits, and these were utilized in the synthesis of higher order dimer, trimer, and tetramer libraries. Several of the most active EPOr binders were found to be partial agonists and induced concentration-dependent proliferation of an EPO-dependent cell line (UT-7/EPO) while having no effect on a cell line lacking the EPOr (FDC-P1). An additional compound library, based on a symmetrical isoindoline-5,6-dicarboxylic acid template and including the optimized binding subunits, was synthesized and screened leading to the identification of additional EPO mimetics.

Cell Division↗
PubMed2006

Stabilization of the activated alphaMbeta2 integrin by a small molecule inhibits leukocyte migration and recruitment.

Integrins are potential targets for the development of antiinflammatory agents. Here we develop a novel high-throughput assay by allowing a chemical library to compete with phage display peptide binding and identify a novel small-molecule ligand to the leukocyte-specific alpha(M)beta(2) integrin. The identified thioxothiazolidine-containing compound, IMB-10, had an unexpected activity in that it stabilized binding of alpha(M)beta(2) to its endogenous ligands proMMP-9 and fibrinogen. Single amino acid substitutions in the activity-regulating C-terminal helix and the underlying region in the ligand-binding I domain of the integrin suppressed the effect of IMB-10. A computational model indicated that IMB-10 occupies a distinct cavity present only in the activated form of the integrin I domain. IMB-10 inhibited alpha(M)beta(2)-dependent migration in vitro and inflammation-induced neutrophil emigration in vivo. Stabilization of integrin-mediated adhesion by a small molecule is a novel means to inhibit cell migration and may have a utility in treatment of inflammatory diseases involving leukocyte recruitment.

Amino Acid Sequence↗
PubMedDate not supplied

Applications of pulsed ultrafiltration-mass spectrometry.

Pulsed ultrafiltration-mass spectrometry (PUF-MS) is a method with a variety of uses for the discovery and development of biologically active small molecules, including the screening of combinatorial libraries and natural product extracts for biologically active compounds, investigation of thermodynamic and kinetic ligand-receptor binding parameters, high-throughput metabolic screening, and the screening of combinatorial libraries and botanical extracts for electrophilic metabolites. Solution-phase ligand-screening assays that use pulsed ultrafiltration-mass spectrometry are useful for "reverse pharmacology" studies in which a macromolecular receptor of interest has been isolated, but ligands for the receptor are needed. Protein-binding studies that involve pulsed ultrafiltration can be used to rapidly determine classical binding parameters for interactions between a macromolecular receptor and a compound of interest. Metabolic screening assays can identify substrates for cytochromes p450, and should be capable of characterizing phase I metabolites with a throughput of at least 60 compounds/hr. Pulsed ultrafiltration can also be used in conjunction with LC-MS-MS to screen mixtures for compounds that might be activated metabolically to electrophilic quinoid and epoxide metabolites by cytochrome p450; that screening can provide early warning of compounds likely to be toxic when administered in large doses. The combination of pulsed-ultrafiltration extraction and mass spectrometric detection provides the sensitivity and selectivity necessary to characterize compounds present at low concentrations in complex chemical mixtures, and is applicable to the analysis of biologically active compounds from combinatorial libraries and botanical extracts.

Animals↗
PubMed2004

PREDICT modeling and in-silico screening for G-protein coupled receptors.

G-protein coupled receptors (GPCRs) are a major group of drug targets for which only one x-ray structure is known (the nondrugable rhodopsin), limiting the application of structure-based drug discovery to GPCRs. In this paper we present the details of PREDICT, a new algorithmic approach for modeling the 3D structure of GPCRs without relying on homology to rhodopsin. PREDICT, which focuses on the transmembrane domain of GPCRs, starts from the primary sequence of the receptor, simultaneously optimizing multiple 'decoy' conformations of the protein in order to find its most stable structure, culminating in a virtual receptor-ligand complex. In this paper we present a comprehensive analysis of three PREDICT models for the dopamine D2, neurokinin NK1, and neuropeptide Y Y1 receptors. A shorter discussion of the CCR3 receptor model is also included. All models were found to be in good agreement with a large body of experimental data. The quality of the PREDICT models, at least for drug discovery purposes, was evaluated by their successful utilization in in-silico screening. Virtual screening using all three PREDICT models yielded enrichment factors 9-fold to 44-fold better than random screening. Namely, the PREDICT models can be used to identify active small-molecule ligands embedded in large compound libraries with an efficiency comparable to that obtained using crystal structures for non-GPCR targets.

Algorithms↗
PubMed2000

A scintillation proximity assay for poly(ADP-ribose) polymerase.

Poly(ADP-ribose) polymerase (PARP) is an abundant nuclear protein in most of the eukaryotic tissues. When activated by DNA damage, PARP synthesizes poly(ADP-ribose) from NAD. Conventional radioactive PARP enzyme assay requires the separation of the polymer product from the NAD substrate, a rate-limiting step that hampers large-scale chemical library screening to identify novel small-molecule PARP inhibitors. By using biotinylated NAD, we have developed a scintillation proximity assay (SPA) for PARP. We demonstrated that PARP can incorporate the biotinylated ADP-ribose units into the radioactive poly(ADP-ribose) polymer, which can directly bind and excite the streptavidin-conjugated scintillation beads. PARP-SPA can be readily adapted to a 96-well format for automatic high-throughput screening for PARP inhibitors.

Animals↗
PubMed1987

Sequence organization of repetitive sequences enriched in small polydisperse circular DNAs from HeLa cells.

A total of 36 clones were randomly selected from a recombinant DNA library of small polydisperse circular DNA (spcDNA) molecules from HeLa cells and were shown to contain repetitive sequences of different reiteration frequencies that ranged from several hundred to several hundred thousand per genome. Sequencing of representative clones revealed tandem repeats of alphoid (alpha) satellite DNA, clustered repeats of the Alu family, KpnI family sequences, tandem repeats of an alpha satellite DNA specific to the X chromosome (alpha X), and A + T-rich segments carrying short stretches of poly(A) or poly(T). DNA rearrangement was frequently found in the repetitive sequences enriched in these spcDNA clones. Short regions of homology that were patchy and inverted were often found, especially at the novel joint where spcDNA sequences are circularized. The presence of these inverted repeats suggests that HeLa spcDNAs are formed by a mechanism that involves looping out of the spcDNA region and joining of the flanking DNA by illegitimate recombination.

Base Sequence↗
PubMed2002

Nucleic acid aptamers in cancer medicine.

Many signalling proteins involved in diverse functions such as cell growth and differentiation can act as oncogenes and cause cellular transformation. These molecules represent attractive targets for cancer diagnosis or therapy and are therefore subject to intensive investigation. Aptamers are small nucleic acid molecules, isolated from combinatorial libraries by a procedure termed SELEX, that bind to a target molecule by providing a limited number of specific contact points embedded in a larger, defined three-dimensional structure. In some cases aptamers have the potential to inhibit the biological function of the molecule resulting in useful reagents for target validation in a variety of disease models.

Animals↗