Success Stories

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 […]

A Cell-Based Assay for I κ B α Stabilization Using A Two-Color Dual Luciferase-Based Sensor

ASSAY and Drug Development Technologies

Davis RE, Zhang Y, Southall N, Staudt LM, Austin CP, Inglese J, Auld DS
ASSAY and Drug Development Technologies - vol. 5 85-104 (2007)

Antifungal chemical compounds identified using a C. elegans pathogenicity assay

PLoS Pathogens

Breger J, Fuchs BB, Aperis G, Moy TI, Ausubel FM, Mylonakis E
PLoS Pathogens - vol. 3 0168-0178 (2007)

There is an urgent need for the development of new antifungal agents. A facile in vivo model that evaluates libraries of chemical compounds could solve some of the main obstacles in current antifungal discovery. We show that Candida albicans, as well as other Candida species, are ingested by Caenorhabditis elegans and establish a persistent lethal […]

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 […]

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 […]

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 […]

Selective optimization of side activities: The SOSA approach

Drug Discovery Today

Wermuth CG
Drug Discovery Today - vol. 11 160-164 (2006)

Selective optimization of side activities of drug molecules (the SOSA approach) is an intelligent and potentially more efficient strategy than HTS for the generation of new biological activities. Only a limited number of highly diverse drug molecules are screened, for which bioavailability and toxicity studies have already been performed and efficacy in humans has been […]

Benzethonium chloride: A novel anticancer agent identified by using a cell-based small-molecule screen

Clinical Cancer Research

Yip KW, Mao X, Au PYB, Hedley DW, Chow S, Dalili S, Mocanu JD, Bastianutto C, Schimmer A, Liu FF
Clinical Cancer Research - vol. 12 5557-5569 (2006)

PURPOSE:This study aims to identify a novel therapeutic agent for head and neck cancer and to evaluate its antitumor efficacy.nnEXPERIMENTAL DESIGN:A cell-based and phenotype-driven high-throughput screening of approximately 2,400 biologically active or clinically used compounds was done using a tetrazolium-based assay on FaDu (hypopharyngeal squamous cancer) and NIH 3T3 (untransformed mouse embryonic fibroblast) cells, with […]