Permeation of permanently positive charged molecules through artificial membranes-Influence of physico-chemical properties

European Journal of Pharmaceutical Sciences

Fischer H, Kansy M, Avdeef A, Senner F
European Journal of Pharmaceutical Sciences - vol. 31 32-42 (2007)

The aim of this study was to investigate the permeation properties of 20 permanently positive charged molecules in the parallel artificial membrane permeability assay (PAMPA). Eight of them were derivatives of the N-alkyl-isoquinolinium salt and 12 were congeners of the dye rhodamine 110. Five out of 12 molecules from the rhodamine 110 series have one […]

A high-throughput screen for aggregation-based inhibition in a large compound library

Journal of Medicinal Chemistry

Feng BY, Simeonov A, Jadhav A, Babaoglu K, Inglese J, Shoichet BK, Austin CP
Journal of Medicinal Chemistry - vol. 50 2385-2390 (2007)

High-throughput screening (HTS) is the primary technique for new lead identification in drug discovery and chemical biology. Unfortunately, it is susceptible to false-positive hits. One common mechanism for such false-positives is the congregation of organic molecules into colloidal aggregates, which nonspecifically inhibit enzymes. To both evaluate the feasibility of large-scale identification of aggregate-based inhibition and […]

Understanding false positives in reporter gene assays: In silico chemogenomics approaches to prioritize cell-based HTS data

Journal of Chemical Information and Modeling

Crisman TJ, Parker CN, Jenkins JL, Scheiber J, Thoma M, Kang ZB, Kim R, Bender A, Nettles JH, Davies JW, Glick M
Journal of Chemical Information and Modeling - vol. 47 1319-1327 (2007)

High throughput screening (HTS) data is often noisy, containing both false positives and negatives. Thus, careful triaging and prioritization of the primary hit list can save time and money by identifying potential false positives before incurring the expense of followup. Of particular concern are cell-based reporter gene assays (RGAs) where the number of hits may […]

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)

Identification of novel inhibitors of UDP-Glc 4???-epimerase, a validated drug target for african sleeping sickness

Bioorganic and Medicinal Chemistry Letters

Urbaniak MD, Tabudravu JN, Msaki A, Matera KM, Brenk R, Jaspars M, Ferguson MAJ
Bioorganic and Medicinal Chemistry Letters - vol. 16 5744-5747 (2006)

Novel inhibitors of Trypanosoma brucei and mammalian UDP-Glc 4???-epimerase were identified by screening a small library of natural products and commercially available drug-like molecules. The inhibitors possess low micromolar potency against the T. brucei and human enzymes in vitro, display a degree of selectivity between the two enzymes, and are cytotoxic to cultured T. brucei […]