|
Articles
|
Brian Y. Feng, Anton Simeonov, Ajit Jadhav, Kerim Babaoglu, James Inglese, Brian K. Shoichet, and Christopher P. Austin
J. Med. Chem., 2007, 50 (10), pp 2385–2390
DOI: 10.1021/jm061317y
Publication Date (Web): April 21, 2007
Abstract
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 quantify its prevalence among screening hits, we tested 70 563 molecules from the National Institutes of Health Chemical Genomics Center (NCGC) library for detergent-sensitive inhibition. Each molecule was screened in at least seven concentrations, such that dose−response curves were obtained for all molecules in the library. There were 1274 inhibitors identified in total, of which 1204 were unambiguously detergent-sensitive. We identified these as aggregate-based inhibitors. Thirty-one library molecules were independently purchased and retested in secondary low-throughput experiments; 29 of these were confirmed as either aggregators or nonaggregators, as appropriate. Finally, with the dose−response information collected for every compound, we could examine the correlation between aggregate-based inhibition and steep dose−response curves. Three key results emerge from this study: first, detergent-dependent identification of aggregate-based inhibition is feasible on the large scale. Second, 95% of the actives obtained in this screen are aggregate-based inhibitors. Third, aggregate-based inhibition is correlated with steep dose−response curves, although not absolutely. The results of this screen are being released publicly via the PubChem database.
|
Drug Discovery News
-
Novel ‘Antisense’ Therapies Protect Primates from Lethal Ebola and Marburg Viruses
ScienceDaily (Aug. 23, 2010) — New studies show that treatments targeting specific viral genes protected monkeys infected with deadly Ebola or Marburg viruses. Furthermore, the animals were protected even when therapeutics were administered one hour after exposure — suggesting the approach holds promise for treating accidental infections in laboratory or hospital settings. See Also: Health [...]
-
Molecular Target for Screening: G-Protein-Coupled Receptors
Newark, DE. August, 2010 – Press Release – TimTec, LLC. – Molecular Target for Screening: G-Protein-Coupled Receptors, ActiTarg-G G-Protein-Coupled Receptors are the largest gene families in the human genome and, rightfully so, have become the leading molecular target in 2008. In 2009 SBS April meeting in Lille, France, followed-up with screening trends report stating that [...]
-
Actelion obtains option to acquire privately-held Trophos
Late-stage Phase III compound in Amyotrophic Lateral Sclerosis to report data in late 2011 – Novel therapeutic approach to be further explored in drug discovery collaboration ALLSCHWIL, SWITZERLAND and MARSEILLE, FRANCE – 20 July 2010 – Actelion Ltd (SIX: ATLN) and privately-held Trophos SA announced today that they have entered into a binding agreement whereby [...]
-
Screen for molecules that inhibit formation of A-beta oligomers
Alzheimer’s disease (AD) is a devastating neurological disorder characterized by the deposition of aggregated proteins in the brain in the form of extracellular beta-amyloid in senile plaques and intracellular tau in neurofibrillary tangles. A current approach towards treatment of Alzheimer’s disease is by using inhibitors of amyloid beta aggregation. Current screening protocols for inhibitors of [...]
-
Nine U.S. Health Research Centers to Receive $255 Million
Nine health research centers have received funds to develop ways to reduce the time it takes for clinical research to become treatments for patients. The funds were awarded as part of the Clinical and Translational Science Awards (CTSA) program which is led by the National Center for Research Resources (NCRR), part of the National Institutes [...]
-
BioFocus and University of Bristol enter drug discovery collaboration in chronic pain
Saffron Walden and Bristol, UK; 16 July 2010 – BioFocus and the University of Bristol today announced a new drug discovery collaboration aimed at developing treatments for chronic pain associated with diabetes (diabetic neuropathic pain). BioFocus will provide hit-to-lead and lead optimization services for a Wellcome Trust funded program at the University of Bristol. Total [...]
-
NIH Prolongs Compound-Management Arrangement with Galapagos Until End of 2012
NIH has extended its agreement with Galapagos’ service division, BioFocus, for the operation of the Molecular Libraries Small Molecule Repository (MLSMR) through December 2012. Galapagos will thus be eligible to receive up to $8.6 million over the course of the two-year extension. The NIH MLSMR collects samples for high-throughput biological screening and distributes them to [...]
-
Aquapharm and AMRI Enter into a Novel Marine Chemistry Collaboration
Aquapharm Biodiscovery, a leading marine biotechnology company, announced today it has signed a research agreement with Albany Molecular Research to identify novel drug-like compounds and scaffolds with anti-microbial and anti-inflammatory activity from Aquapharm’s marine natural products library derived from its extensive collection of marine micro-organisms.Under the terms of this agreement, drawing on its substantial experience [...]
-
Volatile Organic Compounds (VOCs) on the Gulf Coastline
Resource: EPA – United States Environmental Protection Agency Volatile Organic Compounds (VOCs) on the Gulf Coastline EPA is analyzing air samples for volatile organic compounds (VOCs) – including specifically, benzene, ethylbenzene, toluene, and xylene. EPA is sampling for these pollutants because they are present in oil and because, at elevated concentrations, they may cause health [...]
-
The NIH Molecular Libraries Program: Identifying Chemical Probes for New Medicines
Alice McCarthy In 2003, several program leaders within the National Institutes of Health (NIH) recognized that the results from the recently completed Human Genome Project were a launching pad for further study. Now that scientists knew the genome, how could they determine gene function? In particular, how could scientists find specific biological pathways and targets that [...]
|
|
|
|
Call toll free 1 800 574 7391
|
