PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “combinatorial indexing”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 19 recordsLinked to original sources
PubMed1995

Discovery of a novel tetrahydroacridine acetylcholinesterase inhibitor through an indexed combinatorial library.

BACKGROUND: Methods for the rapid and efficient preparation of drug candidates through combinatorial chemistry are of increasing interest. We have previously reported an indexed combinatorial library method that allows both the preparation and testing of compounds in solution. We set out to apply this method to develop more effective analogs of the known, marketed drug tacrine, an acetylcholinesterase inhibitor. RESULTS: A one-step condensation of cyclohexanones with cyanoanilines to generate tetrahydroacridine pools was developed. The resulting library of (formally) 72 tetrahydroacridines was screened against acetylcholinesterase, and a compound 10-fold more potent than tacrine, 7-nitrotacrine, was discovered. Its increased potency could be readily explained by examining the known structure of the complex of acetylcholinesterase with tetrahydroacridine. CONCLUSIONS: In this work, we have provided a relatively rare example of carbon-carbon bond formation in a pool synthesis and have discovered a potentially useful acetylcholinesterase inhibitor.

Acridines↗
PubMed2000

The synthesis and evaluation of a solution phase indexed combinatorial library of non-natural polyenes for reversal of P-glycoprotein mediated multidrug resistance.

A combinatorial library of polyenes, based on (-)-stipiamide, has been constructed and evaluated for the discovery of new multidrug resistance reversal agents. A palladium coupling was used to react each individual vinyl iodide with a mixture of the seven acetylenes at near 1:1 stoichiometry. The coupling was also used to react each individual acetylene with the mixture of six vinyl iodides to create 13 pools indexed in two dimensions for a total of 42 compounds. Individual compounds were detected at equimolar concentration. The vinyl iodides, made initially using a crotylborane addition to generate the anti1,2-hydroxylmethyl products, were now made using a more efficient norephedrine propionate boron enolate aldol reaction. The indexed approach, ideally suited for cellular assays that involve membrane-bound targets, allowed for the rapid identification of reversal agents using assays with drug-resistant human breast cancer MCF7-adrR cells. Intersections of potent pools identified new compounds with promising activity. Aryl dimension pools showed R = ph and naphthyl as the most potent. The acetylene dimension had R' = phenylalaninol and alaninol as the most potent. Isolated individual compounds, both active and nonpotent, were assayed to confirm the library results. The most potent new compound was 4ek (R = naphthyl, R' = phenylaninol) at 1.45 microM. Other nonnatural individual naphthyl-amide compounds showed potent MDR reversal including the morpholino-amide 4ej (1.69 microM). Synergistic activities attributed to the two ends of the molecule were also identified. Direct interaction with Pgp was established by ATPase and photoaffinity displacement assays. The results indicate that both ends of the polyene reversal agent are involved in Pgp interaction and can be further modified for increased potency.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2025

Transcript-guided targeted cell enrichment for scalable single-nucleus RNA sequencing.

Large-scale single-cell atlases have revealed many aging- and disease-associated cell types, yet these populations are often underrepresented in heterogeneous tissues, limiting detailed molecular analyses. To address this, we developed EnrichSci-a scalable, microfluidics-free platform that combines hybridization chain reaction RNA fluorescence in situ hybridization (FISH) with combinatorial indexing to profile single-nucleus transcriptomes of target cell types with full gene-body coverage. Applied to oligodendrocytes in the aging mouse brain, EnrichSci uncovered aging-associated molecular dynamics across distinct oligodendrocyte subtypes, revealing both shared and subtype-specific gene expression changes. Additionally, we identified aging-associated exon-level signatures missed by conventional gene-level analyses, highlighting post-transcriptional regulation as a critical dimension of cell-state dynamics in aging. By coupling transcript-guided enrichment with a scalable sequencing workflow, EnrichSci provides a versatile approach to decode dynamic regulatory landscapes in diverse cell types from complex tissues.

Animals↗
PubMed2003

Combinatorial discovery of two-photon photoremovable protecting groups.

A design principle for a two-photon photochemically removable protecting group based on sequential one-photon processes has been established. The expected performance of such groups in spatially directed photoactivation/photodeprotection has been shown by a kinetic analysis. One particular molecular class fitting into this design, the nitrobenzyl ethers of o-hydroxycinnamates, has been presented. An initial demonstration of two-photon deprotection of one such group prompted further optimization with respect to photochemical deprotection rate. This was accomplished by the preparation and screening of a 135-member indexed combinatorial library. Optimum performance for lambda >350 nm deprotection in organic solvent was found with 4,5-dialkoxy and -cyano substitution in the nitrobenzyl group and 4-methoxy substitution in the cinnamate.

Cinnamates↗
PubMed2026

Mapping convergent regulators of melanoma drug resistance by PerturbFate.

High-throughput genomic studies have uncovered associations between diverse genetic alterations and disease phenotypes. However, elucidating how perturbations in functionally disparate genes give rise to convergent cellular states remains challenging. Here we present PerturbFate, a high-throughput, cost-effective, combinatorial-indexing single-cell platform that enables systematic interrogation of massively parallel CRISPR interference1 perturbations across the full spectrum of gene regulation, from chromatin remodelling and nascent transcription to steady-state transcriptomic phenotypes. Using PerturbFate, we profiled more than 300,000 cultured melanoma cells to characterize multimodal phenotypic and gene regulatory responses to perturbations in more than 140 vemurafenib resistance-associated genes. We uncovered a shared dedifferentiated cell state marked by convergent cooperative transcription factor activities across diverse genetic perturbations. We further dissected phenotypic responses to perturbations in Mediator complex components, linking module-specific biochemical properties to convergent transcriptional activations. We identified common regulatory nodes that drive similar phenotypic outcomes across distinct genetic perturbations. We also delineated how perturbations in functionally unrelated genes reshape cell state. Thus, PerturbFate establishes a versatile platform for identifying key molecular regulators by anchoring multimodal regulatory dynamics to disease-relevant phenotypes.

Humans↗
PubMed2026

Diversity and evolution of chromatin regulatory states across eukaryotes.

Histone post-translational modifications (hPTMs) are key regulators of chromatin states, influencing gene expression, epigenetic memory and transposable element repression across eukaryotic genomes. While many hPTMs are evolutionarily conserved, the extent to which the chromatin states they define are similarly preserved remains unclear. Here we developed a combinatorial indexing chromatin immunoprecipitation followed by sequencing method to simultaneously profile specific hPTMs across diverse eukaryotic lineages, including amoebozoans, rhizarians, discobans and cryptomonads. Our analyses revealed highly conserved euchromatin states at active gene promoters and gene bodies. In contrast, we observed diverse configurations of repressive heterochromatin states associated with silenced genes and transposable elements, characterized by various combinations of hPTMs such as H3K9me3, H3K27me3 and/or different H3K79 methylations. These findings suggest that, while core hPTMs are ancient and broadly conserved, their functional readout has diversified throughout eukaryotic evolution, shaping lineage-specific chromatin landscapes.

Histones↗
PubMed1993

Complex synthetic chemical libraries indexed with molecular tags.

Combinatorial methods of chemical synthesis allow the creation of molecular libraries having immense diversity. The utility of such libraries is dependent upon identifying the structures of the molecules so prepared. We describe the construction of a peptide combinatorial library, having 117,649 different members, synthesized on beads and indexed with inert chemical tags. These tags are used as a binary code to record the reaction history of each bead. The code can be read directly from a single bead by electron capture capillary gas chromatography. We demonstrate the correct selection of members of the library on the basis of binding to a monoclonal antibody.

Amino Acid Sequence↗
PubMed2005

Combinatorial synthesis and antibacterial evaluation of an indexed chalcone library.

A 120-membered chalcone library has been designed and prepared from six differently substituted acetophenones (A1-A6) and 20 benzaldehydes (B1-B20). The library was subjected to biological studies targeted against six bacterial strains. For the identification of the most-active member(s) of the library, the so-called indexed or positional-scanning method was applied. Six out of 26 sub-libraries, i.e., AL1-AL6, were synthesized by keeping the acetophenone moiety A fixed and using equimolar quantities of the 20 different benzaldehydes. The remaining 20 sub-libraries BL1-BL20 were prepared by keeping the benzaldehyde B component fixed and varying the six acetophenones (Table 1). The bactericidal activities of the resulting sub-libraries were tested and used as indices to the rows or columns of a two-dimensional matrix. Finally, parallel synthesis of 24 specific members with the highest-expected antibacterial activities, present in two sub-libraries, was carried out. These chalcones were screened again, and the results were exploited for establishing the structure-activity relationship (SAR) and the identification of the lead compound, which turned out to be 1,3-bis(2-hydroxyphenyl)prop-2-en-1-one (A2B2) in terms of activity towards Staphylococcus aureus and Bacillus subtilis (Tables 5-7).

Anti-Bacterial Agents↗
PubMed2001

Asymmetric activation of chiral alkoxyzinc catalysts by chiral nitrogen activators for dialkylzinc addition to aldehydes: super high-throughput screening of combinatorial libraries of chiral ligands and activators by HPLC-CD/UV and HPLC-OR/RIU systems.

Asymmetric catalysts, prepared by chiral ligand exchange or chiral modification, can evolve further into highly activated catalysts through engineering with chiral activators. Two new methodologies for "super high-throughput screening" (SHTS) of chiral ligands and activators have been developed as a combination of HPLC-CD/UV (CD/ UV = circular dichroism/ultraviolet spectroscopy) or -OR/RIU (OR/RIU = optical rotation/refractive index unit) with a combinatorial chemistry (CC) factory. With these techniques, the % ee of the product is determined within minutes without separation of the enantiomeric products by using a nonchiral stationary phase. Therefore, those SHTS techniques combined with our 'asymmetric activation' concept can provide a powerful strategy for finding the best activated chiral catalyst.

Journal Article↗
PubMed1999

Comparative molecular similarity index analysis (CoMSIA) to study hydrogen-bonding properties and to score combinatorial libraries.

Comparative molecular field analysis has been applied to a data set of thermolysin inhibitors. Fields expressed in terms of molecular similarity indices (CoMSIA) have been used instead of the usually applied Lennard-Jones- and Coulomb-type potentials (CoMFA). Five different properties, assumed to cover the major contributions responsible for ligand binding, have been considered: steric, electrostatic, hydrophobic, and hydrogen-bond donor or acceptor properties. The statistical evaluation of the field properties by PLS analysis reveals a similar predictive potential to CoMFA. However, significantly improved and easily interpretable contour maps are obtained. The features in these maps intuitively suggest where to modify a molecular structure in terms of physicochemical properties and functional groups in order to improve its binding affinity. They can also be interpreted with respect to the known structural protein environment of thermolysin. Most of the highlighted regions in the maps are mirrored by features in the surrounding environment required for binding. Using the derived correlation model, different members of a combinatorial library designed for thermolysin inhibition have been scored for affinity. The results obtained demonstrate the prediction power of the CoMSIA method.

Hydrogen Bonding↗
PubMed2003

The inverse problems for some topological indices in combinatorial chemistry.

In the original paper, Goldman et al. (2000) launched the study of the inverse problems in combinatorial chemistry, which is closely related to the design of combinatorial libraries for drug discovery. Following their ideas, we investigate four other topological indices, i.e., the sigma-index, the c-index, the Z-index, and the M(1)-index, with a special emphasis on the sigma-index. Like the Wiener index, these four indices are very popular in combinatorial chemistry and reflect many chemical and physical properties. We give algorithmic and analytical solutions for the inverse problems of the four indices. We also show that the SUBTREEVALUE reconstruction problem for the sigma-index is NP-hard.

Algorithms↗
PubMed2004

Frozen glass phase in the multi-index matching problem.

The multi-index matching is an NP-hard combinatorial optimization problem; for two indices it reduces to the well understood bipartite matching problem that belongs to the polynomial complexity class. We use the cavity method to solve the thermodynamics of the multi-index system with random costs. The phase diagram is much richer than for the case of the bipartite matching problem: it shows a finite temperature phase transition to a completely frozen glass phase, similar to what happens in the random energy model. We derive the critical temperature, the ground-state energy density, and properties of the energy landscape and compare the results to numerics based on exact analysis of small systems.

Journal Article↗
PubMed2005

Extremal problems for topological indices in combinatorial chemistry.

Topological indices of molecular graphs are related to several physicochemical characteristics; recently, the inverse problem for some of these indices has been studied, and it has some applications in the design of combinatorial libraries for drug discovery. It is thus very natural to study also extremal problems for these indices, i.e., finding graphs having minimal or maximal index. In this paper, these questions will be discussed for three different indices, namely the sigma-index, the c-index and the Z-index, with emphasis on the sigma-index.

Combinatorial Chemistry Techniques↗
PubMed2003

Mithramycin SK, a novel antitumor drug with improved therapeutic index, mithramycin SA, and demycarosyl-mithramycin SK: three new products generated in the mithramycin producer Streptomyces argillaceus through combinatorial biosynthesis.

To gain initial structure-activity relationships regarding the highly functionalized pentyl side chain attached at C-3 of mithramycin (MTM), we focused on a post-polyketide synthase (post-PKS) tailoring step of the MTM biosynthesis by Streptomyces argillaceus ATCC 12956, which was proposed to be catalyzed by ketoreductase (KR) MtmW. In this last step of the MTM biosynthesis, a keto group of the pentyl side chain is reduced to a secondary alcohol, and we anticipated the generation of an MTM derivative with an additional keto group in the 3-side chain. Insertional inactivation of mtmW, a gene located ca. 8 kb downstream of the mithramycin-PKS genes, yielded an S. argillaceus mutant, which accumulated three new mithramycin analogues, namely mithramycin SA, demycarosyl-mithramycin SK, and mithramycin SK (MTM-SK). The structures of these three compounds confirmed indirectly the proposed role of MtmW in MTM biosynthesis. However, the new mithramycin derivatives bear unexpectedly shorter 3-side chains (ethyl or butyl) than MTM, presumably caused by nonenzymatic rearrangement or cleavage reactions of the initially formed pentyl side chain with a reactive beta-dicarbonyl functional group. The major product, MTM-SK, was tested in vitro against a variety of human cancer cell lines, as well as in an in vitro toxicity assay, and showed an improved therapeutic index, in comparison to the parent drug, MTM.

Antibiotics, Antineoplastic↗
PubMed2001

Enhancement of anti-herpetic activity of glycyrrhizic acid by physiological proteins.

Some enzymes present in biological fluids, such as lysozyme (LYS) and lactoferrin (LAC), are known to possess antibacterial and antiviral activity, against herpesviruses in particular. It will be shown in this paper that their combination with a natural triterpene, namely glycyrrhizic acid (GLA), gives significant results in enhancing the antagonistic activity on HSV1 in in vitro assays. Data elaboration was carried out by calculation of the FIC index (fractional inhibitory concentration) for each combination of the three compounds and by a three-dimensional evaluation of the inhibiting combinatory effects, which indicated the percentage of the synergistic action. A FIC index equal to or below 0.5 demonstrated a significant synergistic effect between two substances. Considering each single compound, the 50% inhibiting doses on viral replication (ID50) were 252+/-53 microg/ml for LAC, 497+/-165 microg/ml for LYS and 740+/-125 microg/ml for GLA. The combination of LAC and GLA showed a clear synergistic effect, with a FIC index of 0.08 and a potentiating activity which, for some doses, was up to 1.5 log10 of difference (from about 5.5x10(6) to 10(5) pfu/ml). The combinations of GLA and LYS, and LYS and LAC showed a less significant synergistic activity. These findings led to the conclusion that some physiological proteins, even at concentrations usually present in some body fluids, may enhance the anti-herpetic activity of a natural compound such as GLA.

Animals↗
PubMed2004

Whole-genome expression profiling through fragment display and combinatorial gene identification.

There is a growing demand for highly parallel gene expression analysis with whole genome coverage, high sensitivity and high accuracy. Open systems such as differential display are capable of analyzing most of the expressed genome but are not quantitative and generally require manual identification of differentially expressed genes by sequencing. Closed systems such as microarrays use gene-specific probes and are, therefore, limited to studying specific genes in well-characterized species. Here, we describe Tangerine, a PCR-based system that combines the scope and generality of open systems with a robust and immediate identification algorithm using publicly available sequence information. By combinatorial analysis of three independent and complete DNA indexing profiles, each displaying the complete set of expressed transcripts on capillary electrophoresis, the method allows transcripts to be simultaneously quantified and identified. The method is sensitive, accurate and reproducible, and is amenable to high-throughput automated operation.

Animals↗
PubMedDate not supplied

Drug-like index: a new approach to measure drug-like compounds and their diversity.

Combinatorial organic synthesis (combinatorial chemistry or CC) and ultrahigh-throughput screening (UHTS) are speeding up drug discovery by increasing capacity for making and screening large numbers of compounds. However, a key problem is to select the smaller set of "representative" compounds from a virtual library to make or screen. Our approach is to select drug-like as well as structurally diverse compounds. The compounds, which are not very drug-like, are less taken into account or excluded even if they contribute to the diversity of the collection. Hence, the first step in the compound selection is to rank compounds in drug-like "degree". To quantify the drug-like "degree", drug-like index (DLI) is introduced in this paper. A compound's DLI is calculated based upon the knowledge derived from known drugs selected from Comprehensive Medicinal Chemistry (CMC) database. The paper describes the way of this knowledge base is formed and the procedure for selecting drug-like compounds.

Algorithms↗