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 […]

Integration of Virtual Screening with High-Throughput Flow Cytometry to Identify Novel Small Molecule Formylpeptide

Molecular pharmacology

Edwards BS, Bologa C, Young SM, Balakin KV, Prossnitz ER, Savchuck NP, Sklar LA, Oprea TI
Molecular pharmacology - vol. 68 1301-1310 (2005)

Receptor Binding Techniques

Nethods in Molecular Biology

Tobergte DR, Curtis S
Nethods in Molecular Biology - vol. Second Edi 17-25 (2005)

applicability for this approach.

Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation.

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

Ray SS, Nowak RJ, Brown RH, Lansbury PT
Proceedings of the National Academy of Sciences of the United States of America - vol. 102 3639-3644 (2005)

Familial amyotrophic lateral sclerosis (FALS) is a fatal motor neuron disease that is caused by mutations in the gene encoding superoxide dismutase-type 1 (SOD1). The affected regions of the FALS brain are characterized by aggregated SOD1, and the mutations that destabilize SOD1 appear to promote its aggregation in vitro. Because dissociation of the native SOD1 […]

Finding New Tricks For Old Drugs: An Efficient Route For Public-Sector Drug Discovery

Nat Rev Drug Discov

O'Connor KA, Roth BL
Nat Rev Drug Discov - vol. 4 1005-1014 (2005)

With the annotation of the human genome approaching completion, public-sector researchers – spurred in part by various National Institutes of Health Roadmap Initiatives – have become increasingly engaged in drug discovery and development efforts. Although large and diverse chemical libraries of ‘drug-like’ compounds can be readily screened to yield chemically novel scaffolds, transforming these ‘chemical […]

Nystatin induces secretion of interleukin (IL)-1??, IL-8, and tumor necrosis factor alpha by a toll-like receptor-dependent mechanism

Antimicrobial Agents and Chemotherapy

Razonable RR, Henault M, Watson HL, Paya CV
Antimicrobial Agents and Chemotherapy - vol. 49 3546-3549 (2005)

Nystatin is an antifungal compound with potent proinflammatory properties. Herein, we demonstrate that nystatin induces interleukin (IL)-1beta, IL-8, and tumor necrosis factor alpha secretion through its activation of toll-like receptor 1 (TLR1) and TLR2. Hence, a TLR-dependent mechanism could serve as the molecular basis for the proinflammatory properties of nystatin.