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

Molecular Diversity

Monge A, Arrault A, Marot C, Morin-Allory L
Molecular Diversity - vol. 10 389-403 (2006)

The data for 3.8 million compounds from structural databases of 32 providers were gathered and stored in a single chemical database. Duplicates are removed using the IUPAC International Chemical Identifier. After this, 2.6 million compounds remain. Each database and the final one were studied in term of uniqueness, diversity, frameworks, ‘drug-like’ and ‘lead-like’ properties. This […]

Inhibition of the enzymatic activity of heme oxygenases by azole-based antifungal drugs.

The Journal of pharmacology and experimental therapeutics

Kinobe RT, Dercho RA, Vlahakis JZ, Brien JF, Szarek WA, Nakatsu K
The Journal of pharmacology and experimental therapeutics - vol. 319 277-284 (2006)

Ketoconazole (KTZ) and other azole antifungal agents are known to have a variety of actions beyond the inhibition of sterol synthesis in fungi. These drugs share structural features with a series of novel heme oxygenase (HO) inhibitors designed in our laboratory. Accordingly, we hypothesized that therapeutically used azole-based antifungal drugs are effective HO inhibitors. Using […]

Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries.

Proceedings of the National Academy of Sciences of the United States of America

Inglese J, Auld DS, Jadhav A, Johnson RL, Simeonov A, Yasgar A, Zheng W, Austin CP
Proceedings of the National Academy of Sciences of the United States of America - vol. 103 11473-11478 (2006)

High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently […]

Two approaches to drug discovery in SOD1-mediated ALS.

Journal of biomolecular screening

Broom WJ, Auwarter KE, Ni J, Russel DE, Yeh L, Maxwell MM, Glicksman M, Kazantsev AG, Brown RH
Journal of biomolecular screening - vol. 11 729-35 (2006)

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS cases; approximately 25% of these cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). To date, 105 different mutations spanning all 5 exons have been identified in the SOD1 gene. Mutant SOD1-associated ALS is caused by a toxic gain of function […]

Use of a fluorescent polarization based high throughput assay to identify new Calmodulin ligands

Biochimica et Biophysica Acta - Molecular Cell Research

Dagher R, Pigault C, Bonnet D, Boeglin D, Pourbaix C, Kilhoffer MC, Villa P, Wermuth CG, Hibert M, Haiech J
Biochimica et Biophysica Acta - Molecular Cell Research - vol. 1763 1250-1255 (2006)

In order to develop a fluorescence polarization (FP) assay for calcium binding proteins, a fluorescent peptides based library of 1328 compounds has been synthesized. The use of this library has been validated by setting up a FP-high-throughput screening (FP-HTS) assay for calmodulin using the synthetic gene product (synCaM). With this assay, a set of 880 […]

Obtaining and screening compound collections: a user’s guide and a call to chemists

Current Opinion in Chemical Biology

Hergenrother PJ
Current Opinion in Chemical Biology - vol. 10 213-218 (2006)

Advances in genetics, proteomics and cell biology over the past 20 years have unearthed a multitude of potential macromolecular targets for the selective treatment of disease. The challenge remains to find appropriate small molecule ligands for these proteins (or nucleic acids), and to use these ligands to validate novel disease targets. The advent of low-cost […]

Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak

PLoS Medicine

Schuffenecker I, Iteman I, Michault A, Murri S, Frangeul L, Vaney MC, Lavenir R, Pardigon N, Reynes JM, Pettinelli F, Biscornet L, Diancourt L, Michel S, Duquerroy S, Guigon G, Frenkiel MP, Br??hin AC, Cubito N, Despr??s P, Kunst F, Rey FA, Zeller H, Brisse S
PLoS Medicine - vol. 3 1058-1070 (2006)

BACKGROUND: A chikungunya virus outbreak of unprecedented magnitude is currently ongoing in Indian Ocean territories. In Réunion Island, this alphavirus has already infected about one-third of the human population. The main clinical symptom of the disease is a painful and invalidating poly-arthralgia. Besides the arthralgic form, 123 patients with a confirmed chikungunya infection have developed […]

Rational design of macrolides by virtual screening of combinatorial libraries generated through in silico manipulation of polyketide synthases

Journal of Medicinal Chemistry

Zotchev SB, Stepanchikova AV, Sergeyko AP, Sobolev BN, Filimonov DA, Poroikov VV
Journal of Medicinal Chemistry - vol. 49 2077-2087 (2006)

Bacterial secondary metabolites display diverse biological activities, thus having potential as pharmacological agents. Although most of these compounds are discovered by random screening, it is possible to predict and re-design their structures based on the information on their biosynthetic pathways. Biosynthesis of macrolides, governed by modular polyketide synthases (PKS), obeys certain rules, which can be […]

Similarity in drugs: reflections on analogue design

Drug Discovery Today

Wermuth CG
Drug Discovery Today - vol. 11 348-354 (2006)

A survey of novel small-molecule therapeutics reveals that the majority of them result from analogue design and that their market value represents two-thirds of all small-molecule sales. In natural science, the term analogue, derived from the Latin and Greek analogia, has always been used to describe structural and functional similarity. Extended to drugs, this definition […]

Development and Validation of a High-Throughput Screen for Inhibitors of SARS CoV and Its Application in Screening of a 100,000-Compound Library

Journal of Biomolecular Screening

Severson WE, Shindo N, Sosa M, Fletcher T, White EL, Ananthan S, Jonsson CB
Journal of Biomolecular Screening - vol. 12 33-40 (2006)