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SUMMARYThere is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against M. tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein. CONFLICT OF INTEREST STATEMENTCompeting interests: Dr. Goldman is a NIAID staff member who either in the past or currently provides oversight for the project that generated the data used as the basis for this work.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public AccessAuthor Manuscript Tuberculosis (Edinb) The MLSCN was established in 2005 as a pilot program to assemble a large library of biologically relevant small molecules and make them available through a network of HTS laboratories to researchers worldwide through a competitive assay submission process. Acceptance of the TAACF assay into the MLSCN program made available the unique resources of the NIH Small Molecule Repository (SMR), significantly expanding the spectrum of molecules tested for activity against TB. For this screen, a 215,110-compound library from the SMR was examined for anti-TB activity using the assay described previously, 7 with the only change to the screening protocol being the elimination of the polyethylene incubator bags, resulting in the identification of a number of novel chemical scaffolds. Moreover, even for classes of compounds identified earlier during testing of the NIAID ChemBridge library, 7 additional examples emerged that further clarified the structure-activity picture. Since the compounds in the SMR have been examined in scores of diverse assays undertaken by the MLSCN, and the results published on the NIH PubChem website, 8 another motivation for conducting the MLSCN campaign is the ability to correlate antituberculosis activity of the hits with other biological activities that these compounds may possess, potentially providing information about possible mechanisms of action or toxicity. The raw screening results upon which the structural analysis below is based are now publicly available on PubChem (assay AIDs 1332 and 1626). MATERIALS ...

Small-molecule probes can illuminate biological processes and aid in the assessment of emerging therapeutic targets by perturbing biological systems in a manner distinct from other experimental approaches. Despite the tremendous promise of chemical tools for investigating biology and disease, small-molecule probes were unavailable for most targets and pathways as recently as a decade ago. In 2005, the U.S. National Institutes of Health launched the decade-long Molecular Libraries Program with the intent of innovating in and broadening access to small-molecule science. This Perspective describes how novel small-molecule probes identified through the program are enabling the exploration of biological pathways and therapeutic hypotheses not otherwise testable. These experiences illustrate how small-molecule probes can help bridge the chasm between biological research and the development of medicines, but also highlight the need to innovate the science of therapeutic discovery.

A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

Summary Kinase targets are being pursued in a variety of diseases beyond cancer, including immune and metabolic as well as viral, parasitic, fungal and bacterial. In particular, there is a relatively recent interest in kinase and ATP-binding targets in Mycobacterium tuberculosis in order to identify inhibitors and potential drugs for essential proteins that are not targeted by current drug regimens. Herein, we report the high throughput screening results for a targeted library of approximately 26,000 compounds that was designed based on current kinase inhibitor scaffolds and known kinase binding sites. The phenotypic data presented herein may form the basis for selecting scaffolds/compounds for further enzymatic screens against specific kinase or other ATP-binding targets in Mycobacterium tuberculosis based on the apparent activity against the whole bacteria in vitro.