Success Stories

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 […]

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 […]

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.

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 […]

( 19 ) United States ( 12 ) Patent Application Publication ( 10 ) Pub . No .: US 2010 / 0041620 A1 Publication Classi ? cation 6 Weak Followup Patent Application Publication

Ruebel S, Stuemke M
- vol. 1 11 (2004)

The invention relates to a bath for the electrodeposition of gold and gold alloys and to its use for producing dental moldings. In this bath, the gold is in the form of a gold sul?te complex. The bath according to the invention and/or the use according to the invention is distinguished by the fact that […]