Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers

Monge, Aurélien; Arrault, Alban; Marot, Christophe; Morin‐Allory, Luc

doi:10.1007/s11030-006-9033-5

Cited by 64 publications

(48 citation statements)

References 38 publications

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“…False positives due to the quenching of AMC amine fluorescence were eliminated by a series of control experiments in which each compound was incubated at a concentration of 10 μmol/L with a 200 nmol/L AMC amine solution. The assay was optimized and a proprietary compound library of 65,092 chemically diverse compounds was screened for USP7 activity (23).…”

Section: Methodsmentioning

confidence: 99%

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells

Colland

Formstecher

Jacq

et al. 2009

Molecular Cancer Therapeutics

293

242

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Deregulation of the ubiquitin/proteasome system has been implicated in the pathogenesis of many human diseases, including cancer. Ubiquitin-specific proteases (USP) are cysteine proteases involved in the deubiquitination of protein substrates. Functional connections between USP7 and essential viral proteins and oncogenic pathways, such as the p53/Mdm2 and phosphatidylinositol 3-kinase/protein kinase B networks, strongly suggest that the targeting of USP7 with small-molecule inhibitors may be useful for the treatment of cancers and viral diseases. Using high-throughput screening, we have discovered HBX 41,108, a small-molecule compound that inhibits USP7 deubiquitinating activity with an IC 50 in the submicromolar range. Kinetics data indicate an uncompetitive reversible inhibition mechanism. HBX 41,108 was shown to affect USP7-mediated p53 deubiquitination in vitro and in cells. As RNA interference-mediated USP7 silencing in cancer cells, HBX 41,108 treatment stabilized p53, activated the transcription of a p53 target gene without inducing genotoxic stress, and inhibited cancer cell growth. Finally, HBX 41,108 induced p53-dependent apoptosis as shown in p53 wild-type and null isogenic cancer cell lines. We thus report the identification of the first lead-like inhibitor against USP7, providing a structural basis for the development of new anticancer drugs.

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Section: Methodsmentioning

confidence: 99%

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells

Colland

Formstecher

Jacq

et al. 2009

Molecular Cancer Therapeutics

293

242

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“…Second, it depends on the size of the database. In general, the larger the database, the more likelihood to have more scaffolds making difficult a meaningful comparison of libraries of different size [13,25]. However, we and others have shown that large combinatorial libraries may contain a very low proportion of scaffolds as compared to smaller collections [12,18].…”

Section: Introductionmentioning

confidence: 95%

Scaffold Diversity Analysis of Compound Data Sets Using an Entropy‐Based Measure

et al. 2009

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Scaffold diversity analysis of compound databases has multiple applications in medicinal chemistry and drug discovery including library design, compounds acquisition, virtual screening and assessment of structure-activity-relationships. The scaffold diversity is commonly measured based on frequency counts. Further information can be obtained by considering the specific distribution of the molecules in those scaffolds. To this end, we introduce in this work the use of an entropy-based information metric to assess the scaffold diversity of compound data sets. As a test case we analyzed the scaffold diversity of 16 data sets of active compounds comparable in size targeting five protein classes of interest in drug design. The diversity was also assessed in terms of frequency counts and scaffold retrieval curves. The entropy-based information metric takes into account the frequency distribution of the different scaffolds and is a complementary measure of scaffold diversity enabling a more comprehensive analysis.

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“…Em teoria, estes derivados possuem bom potencial para apresentar atividade antimalárica, somado a um bom perfil de segurança. O potencial de cada um como protótipo foi avaliado utilizando um escore (lead-like score) calculado no programa Dragon 6, baseado nos parâmetros propostos por Monge et al 54 Para os quatro compostos, foi obtido o valor ideal de 1. Ou seja, nenhum dos parâmetros moleculares utilizados para a obtenção do escore foi violado, indicando que os quatro compostos são protótipos em potencial.…”

Section: Figura 4 Resultados Dos Estudos De Validação Cruzada Lno (Aunclassified

COMPUTACIONAL STUDY OF 1H-IMIDAZOL-2-YL-PYRIMIDINE-4,6-DIAMINES FOR IDENTIFICATION OF POTENTIAL PARENT COMPOUNDS OF NEW ANTIMALARIAL AGENTS

2016

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Recebido em 24/10/2015; aceito em 01/02/2016; publicado na web em 15/04/2016 COMPUTACIONAL STUDY OF 1H-IMIDAZOL-2-YL-PYRIMIDINE-4,6-DIAMINES FOR IDENTIFICATION OF POTENTIAL PARENT COMPOUNDS OF NEW ANTIMALARIAL AGENTS. The aim of this study was develop in silico studies with a data set of 1H-imidazol-2-yl-pyrimidine-4,6-diamines derivatives described as antimalarial agents with the intention of obtain data and tools useful in the development of new drugs of this class. A QSAR model was developed using topological, geometrical and electronic molecular descriptors with aid of the OPS/PLS approach. The data set was also used for pharmacophoric modeling, that was used in the ZINC database for found compounds that show good fit with the model. Due to the similarity between the four selected hits in the virtual screening with the data set, the obtained equation was used for predict the potential antimalarial activity. All hits were within the applicablity domain of the QSAR model, and showed adquates Monge's leadlikeness score and predicted safety profiles.

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Managing, profiling and analyzing a library of 2.6 million compounds gathered from 32 chemical providers

Cited by 64 publications

References 38 publications

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells

Small-molecule inhibitor of USP7/HAUSP ubiquitin protease stabilizes and activates p53 in cells

Scaffold Diversity Analysis of Compound Data Sets Using an Entropy‐Based Measure

COMPUTACIONAL STUDY OF 1H-IMIDAZOL-2-YL-PYRIMIDINE-4,6-DIAMINES FOR IDENTIFICATION OF POTENTIAL PARENT COMPOUNDS OF NEW ANTIMALARIAL AGENTS

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