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 […]

Integration of virtual and physical screening

Drug Discovery Today: Technologies

Fara DC, Oprea TI, Prossnitz ER, Bologa CG, Edwards BS, Sklar LA
Drug Discovery Today: Technologies - vol. 3 377-385 (2006)

High-throughput screening (HTS) represents the dominant technique for the identification of new lead compounds in current drug discovery. It consists of physical screening (PS) of large libraries of chemicals against one or more specific biological targets. Virtual screening (VS) is a strategy for in silico evaluation of chemical libraries for a given target, and can […]

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 […]

A High-Throughput Drug Screen Targeted to the 5’Untranslated Region of Alzheimer Amyloid Precursor Protein mRNA

Journal of Biomolecular Screening

Bandyopadhyay S
Journal of Biomolecular Screening - vol. 11 469-480 (2006)

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.

Methylxanthine drugs are chitinase inhibitors: Investigation of inhibition and binding modes

Chemistry and Biology

Rao FV, Andersen OA, Vora KA, DeMartino JA, Van Aalten DMF
Chemistry and Biology - vol. 12 973-980 (2005)

Family 18 chitinases play key roles in a range of pathogenic organisms and are overexpressed in the asthmatic lung. By screening a library of marketed drug molecules, we have identified methylxanthine derivatives as possible inhibitor leads. These derivatives, theophylline, caffeine, and pentoxifylline, are used therapeutically as antiinflammatory agents, with pleiotropic mechanisms of action. Here it […]

HERG-Lite??: A novel comprehensive high-throughput screen for drug-induced hERG risk

Journal of Pharmacological and Toxicological Methods

Wible BA, Hawryluk P, Ficker E, Kuryshev YA, Kirsch G, Brown AM
Journal of Pharmacological and Toxicological Methods - vol. 52 136-145 (2005)

Introduction: Direct block of IKr by non-antiarrhythmic drugs (NARDs) is a major cause of QT prolongation and torsades de pointes (TdP), and has made the hERG potassium channel a major target of drug safety programs in cardiotoxicity. Block of hERG currents is not the only way that drugs can adversely impact the repolarizing current IKr, […]

Development of a mechanism-based assay for tissue transglutaminase – Results of a high-throughput screen and discovery of inhibitors

Analytical Biochemistry

Case A, Ni J, Yeh LA, Stein RL
Analytical Biochemistry - vol. 338 237-244 (2005)

Tissue transglutaminase (TGase) is a Ca2+-dependent enzyme that catalyzes cross-linking of intracellular proteins through a mechanism that involves isopeptide bond formation between Gln and Lys residues. In addition to its transamidation activity, TGase can bind guanosine 5???-triphosphate (GTP) and does so in a manner that is antagonized by calcium. Once bound, GTP undergoes hydrolysis to […]