NIH Molecular Libraries Initiative

Austin, Christopher P.; Brady, Linda S.; Insel, Thomas R.; Collins, Francis S.

doi:10.1126/science.1105511

Cited by 324 publications

(250 citation statements)

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“…The recent creation of a molecular library screening centers network (MLSCN) in universities and the NIH has, for the first time, encouraged academic investigators to engage in the early phase of identifying small molecules for influencing specific cellular pathways. 30 The MLSCN uses a library of small molecules, an array of assays recommended by the field, and high throughput screening centers to identify 'hits' for any given target. Of course, there will be a vast amount of medicinal chemistry necessary to translate a 'hit' in a small molecule screen into a drug, but this network promises to increase the number and the range of targets that can be interrogated.…”

Section: A Different Approachmentioning

confidence: 99%

Cure therapeutics and strategic prevention: raising the bar for mental health research

2005

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Mental disorders cause more disability than any other class of medical illness in Americans between ages 15 and 44 years. The suicide rate is higher than the annual mortality from homicide, AIDS, and most forms of cancer. In contrast to nearly all communicable and most non-communicable diseases, there is little evidence that the morbidity and mortality from mental disorders have changed in the past several decades. Mental health advocates, including psychiatric researchers, have pointed to stigma as one of the reasons for the lack of progress with mental illnesses relative to other medical illnesses. This review considers how the expectations and goals of the research community have contributed to this relative lack of progress. In contrast to researchers in cancer and heart disease who have sought cures and preventions, biological psychiatrists in both academia and industry have set their sights on incremental and marketable advances, such as drugs with fewer adverse effects. This essay argues for approaches that can lead to cures and strategies for prevention of schizophrenia and mood disorders.

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Section: A Different Approachmentioning

confidence: 99%

Cure therapeutics and strategic prevention: raising the bar for mental health research

2005

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“…These results demonstrate the ability of qHTS to rapidly identify new in vitro chemical probes and produce comprehensive librarybioactivity information suitable for initiation of medicinal chemistry for both in vivo chemical probes and drug development (6). By providing reliable measures of compound behavior across biological processes, qHTS generates data sets that can be compared to identify compounds with narrow or wide spectra of bioactivity as well as activities not modulated by current libraries, thus guiding compound library expansion into novel chemical space.…”

mentioning

confidence: 99%

Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries

Inglese

Auld

Jadhav

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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High-throughput screening (HTS) of chemical compounds to identify modulators of molecular targets is a mainstay of pharmaceutical development. Increasingly, HTS is being used to identify chemical probes of gene, pathway, and cell functions, with the ultimate goal of comprehensively delineating relationships between chemical structures and biological activities. Achieving this goal will require methodologies that efficiently generate pharmacological data from the primary screen and reliably profile the range of biological activities associated with large chemical libraries. Traditional HTS, which tests compounds at a single concentration, is not suited to this task, because HTS is burdened by frequent false positives and false negatives and requires extensive follow-up testing. We have developed a paradigm, quantitative HTS (qHTS), tested with the enzyme pyruvate kinase, to generate concentration-response curves for >60,000 compounds in a single experiment. We show that this method is precise, refractory to variations in sample preparation, and identifies compounds with a wide range of activities. Concentration-response curves were classified to rapidly identify pyruvate kinase activators and inhibitors with a variety of potencies and efficacies and elucidate structure-activity relationships directly from the primary screen. Comparison of qHTS with traditional single-concentration HTS revealed a high prevalence of false negatives in the single-point screen. This study demonstrates the feasibility of qHTS for accurately profiling every compound in large chemical libraries (>10 5 compounds). qHTS produces rich data sets that can be immediately mined for reliable biological activities, thereby providing a platform for chemical genomics and accelerating the identification of leads for drug discovery.1,536-well ͉ chemical genomics ͉ enzyme assay ͉ PubChem ͉ pyruvate kinase T he first description of biological effect versus chemical compound concentration was made by Paracelsus ca. 1534 and quantified by A. V. Hill in 1910 (1). The basis of these observations is that ligands affecting biological systems have optimal ranges of activity (EC 50 ), and give rise to concentration-effect relationships that can be complex, varying in potency, efficacy, and steepness of response. Far below an EC 50 , no effect may be seen (referred to as the no observable effect level or NOEL), and much above it, toxic or ''off-target'' effects may be observed. This well known behavior of chemical compounds in biological systems requires a specific dose of a compound to achieve a desired biological effect, whether in basic or clinical applications (2, 3).Historically, new compounds with medicinal qualities were discovered through laborious testing of samples using low-throughput assays including animal and isolated tissue models. In the early 1990s, the advent of combinatorial chemistry and commercial consolidation of small molecule collections resulted in a tremendous increase in compound numbers, requiring the development of high-throughput ...

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“…Such advances could provide Opportunities and challenges of psychiatric drug PJ Conn and BL Roth a major step in discovery of novel therapeutic agents by helping to identify the most viable approaches for further investment in an industrial setting. It has been proposed that initiatives like the NIH Molecular Library Screening Centers Network (MLSCN) will speed discovery for novel therapeutic approaches by providing validated molecular probes for preclinical research (Austin et al, 2004). As has acknowledged by proponents of the MLSCN (Austin et al, 2004;O'Connor and Roth, 2005), however, because of the enormous costs associated with drug discovery and development it is unlikely that new therapeutic agents will arise as a direct result of these screening efforts.…”

Section: Recommendationsmentioning

confidence: 99%

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

Conn

Roth

2008

Neuropsychopharmacol

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Despite significant progress in understanding the biological systems and mechanisms involved in CNS disorders, use of this knowledge to realize practical gains in psychiatric care has been slow. To gain further insight into the reasons for failure and success in CNS drug discovery, preclinical predictors of success and failure for CNS drug discovery were evaluated for drugs developed for schizophrenia, depression, and anxiety. Specifically, we examined the success rate for drugs that had entered at least the later stages of preclinical research. Almost 500 compounds (140 antipsychotic; 211 antidepressant; 143 anxiolytic) were classified based on their molecular target(s) and evaluated based on preclinical validation, whether preclinical studies predicted clinical efficacy, and whether the compound displayed greater efficacy than 'conventional treatment' Results varied with indication but suggest that preclinical models have modest to good ability to predict overall clinical efficacy and adverse effect liability but are less able to predict efficacy greater than conventional treatment. In order to fully realize the potential therapeutic impact of recent basic science discoveries, it will be critical to increase attention on rigorous target validation at each step of the drug discovery process and focus efforts on developing new tools and clinical models that can be used for proof-of-concept studies in early clinical development. Also, increased attention should be focused on the development of early predictors of adverse effects of candidate compounds.

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NIH Molecular Libraries Initiative

Cited by 324 publications

References 12 publications

Cure therapeutics and strategic prevention: raising the bar for mental health research

Cure therapeutics and strategic prevention: raising the bar for mental health research

Quantitative high-throughput screening: A titration-based approach that efficiently identifies biological activities in large chemical libraries

Opportunities and Challenges of Psychiatric Drug Discovery: Roles for Scientists in Academic, Industry, and Government Settings

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