Publications by authors named "Noel T Southall"

18 Publications

  • Page 1 of 1

Predicting liver cytosol stability of small molecules.

J Cheminform 2020 Apr 7;12(1):21. Epub 2020 Apr 7.

National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), 9800 Medical Center Drive, Rockville, MD, 20850, USA.

Over the last few decades, chemists have become skilled at designing compounds that avoid cytochrome P (CYP) 450 mediated metabolism. Typical screening assays are performed in liver microsomal fractions and it is possible to overlook the contribution of cytosolic enzymes until much later in the drug discovery process. Few data exist on cytosolic enzyme-mediated metabolism and no reliable tools are available to chemists to help design away from such liabilities. In this study, we screened 1450 compounds for liver cytosol-mediated metabolic stability and extracted transformation rules that might help medicinal chemists in optimizing compounds with these liabilities. In vitro half-life data were collected by performing in-house experiments in mouse (CD-1 male) and human (mixed gender) cytosol fractions. Matched molecular pairs analysis was performed in conjunction with qualitative-structure activity relationship modeling to identify chemical structure transformations affecting cytosolic stability. The transformation rules were prospectively validated on the test set. In addition, selected rules were validated on a diverse chemical library and the resulting pairs were experimentally tested to confirm whether the identified transformations could be generalized. The validation results, comprising nearly 250 library compounds and corresponding half-life data, are made publicly available. The datasets were also used to generate in silico classification models, based on different molecular descriptors and machine learning methods, to predict cytosol-mediated liabilities. To the best of our knowledge, this is the first systematic in silico effort to address cytosolic enzyme-mediated liabilities.
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http://dx.doi.org/10.1186/s13321-020-00426-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140498PMC
April 2020

Critical Assessment of Artificial Intelligence Methods for Prediction of hERG Channel Inhibition in the "Big Data" Era.

J Chem Inf Model 2020 Dec 1;60(12):6007-6019. Epub 2020 Dec 1.

National Center for Advancing Translational Sciences (NCATS), 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

The rise of novel artificial intelligence (AI) methods necessitates their benchmarking against classical machine learning for a typical drug-discovery project. Inhibition of the potassium ion channel, whose alpha subunit is encoded by the human -related gene (hERG), leads to a prolonged QT interval of the cardiac action potential and is a significant safety pharmacology target for the development of new medicines. Several computational approaches have been employed to develop prediction models for the assessment of hERG liabilities of small molecules including recent work using deep learning methods. Here, we perform a comprehensive comparison of hERG effect prediction models based on classical approaches (random forests and gradient boosting) and modern AI methods [deep neural networks (DNNs) and recurrent neural networks (RNNs)]. The training set (∼9000 compounds) was compiled by integrating the hERG bioactivity data from the ChEMBL database with experimental data generated from an , high-throughput thallium flux assay. We utilized different molecular descriptors including the latent descriptors, which are real-value continuous vectors derived from chemical autoencoders trained on a large chemical space (>1.5 million compounds). The models were prospectively validated on ∼840 compounds screened in the same thallium flux assay. The best results were obtained with the XGBoost method and RDKit descriptors. The comparison of models based only on latent descriptors revealed that the DNNs performed significantly better than the classical methods. The RNNs that operate on SMILES provided the highest model sensitivity. The best models were merged into a consensus model that offered superior performance compared to reference models from academic and commercial domains. Furthermore, we shed light on the potential of AI methods to exploit the big data in chemistry and generate novel chemical representations useful in predictive modeling and tailoring a new chemical space.
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http://dx.doi.org/10.1021/acs.jcim.0c00884DOI Listing
December 2020

Identification of a Small-Molecule Inhibitor That Disrupts the SIX1/EYA2 Complex, EMT, and Metastasis.

Cancer Res 2020 06 27;80(12):2689-2702. Epub 2020 Apr 27.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Metastasis is the major cause of mortality for patients with cancer, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The Sine oculis homeobox homolog 1 (SIX1)/eyes absent (EYA) transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGFβ signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGFC-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction. 8430 partially reversed transcriptional and metabolic profiles mediated by SIX1 overexpression and reversed SIX1-induced TGFβ signaling and EMT. 8430 was well tolerated when delivered to mice and significantly suppressed breast cancer-associated metastasis without significantly altering primary tumor growth. Thus, we have demonstrated for the first time that pharmacologic inhibition of the SIX1/EYA2 complex and associated phenotypes is sufficient to suppress breast cancer metastasis. SIGNIFICANCE: These findings identify and characterize a novel inhibitor of the SIX1/EYA2 complex that reverses EMT phenotypes suppressing breast cancer metastasis.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-0435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510951PMC
June 2020

Freedom of Information Act Access to an Investigational New Drug Application.

Authors:
Noel T Southall

ACS Pharmacol Transl Sci 2019 Dec 20;2(6):497-500. Epub 2019 Aug 20.

National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, United States.

We report our experience working with the US Food and Drug Administration (FDA) to obtain access to an abandoned investigational new drug (IND) application and subsequent application documents submitted by Hoffman-La Roche, Inc. to the agency. Contrary to others' experience and in response to our specific request, FDA provided the IND application number and 464 pages of relevant material, including the initial pharmacology review by the agency and an annual report consisting of an investigational drug brochure, clinical study protocol and amendments and detailing clinical experience with drug treatment. It may be possible to bring application files of additional drugs previously submitted to the agency into the public record to help bolster repurposing efforts and realize our shared public interest in benefiting from previous human clinical studies.
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http://dx.doi.org/10.1021/acsptsci.9b00056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7089016PMC
December 2019

The use or generation of biomedical data and existing medicines to discover and establish new treatments for patients with rare diseases - recommendations of the IRDiRC Data Mining and Repurposing Task Force.

Orphanet J Rare Dis 2019 10 15;14(1):225. Epub 2019 Oct 15.

Chiesi Farmaceutici SpA, Parma, Italy.

The number of available therapies for rare diseases remains low, as fewer than 6% of rare diseases have an approved treatment option. The International Rare Diseases Research Consortium (IRDiRC) set up the multi-stakeholder Data Mining and Repurposing (DMR) Task Force to examine the potential of applying biomedical data mining strategies to identify new opportunities to use existing pharmaceutical compounds in new ways and to accelerate the pace of drug development for rare disease patients. In reviewing past successes of data mining for drug repurposing, and planning for future biomedical research capacity, the DMR Task Force identified four strategic infrastructure investment areas to focus on in order to accelerate rare disease research productivity and drug development: (1) improving the capture and sharing of self-reported patient data, (2) better integration of existing research data, (3) increasing experimental testing capacity, and (4) sharing of rare disease research and development expertise. Additionally, the DMR Task Force also recommended a number of strategies to increase data mining and repurposing opportunities for rare diseases research as well as the development of individualized and precision medicine strategies.
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http://dx.doi.org/10.1186/s13023-019-1193-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794821PMC
October 2019

Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.

FASEB J 2019 11 16;33(11):12435-12446. Epub 2019 Aug 16.

Department of Human and Molecular Genetics, Herbert Wertheim College of Medicine, Florida International University, Miami, Florida, USA.

Fibrosis is an underlying cause of cirrhosis and hepatic failure resulting in end stage liver disease with limited pharmacological options. The beneficial effects of relaxin peptide treatment were demonstrated in clinically relevant animal models of liver fibrosis. However, the use of relaxin is problematic because of a short half-life. The aim of this study was to test the therapeutic effects of recently identified small molecule agonists of the human relaxin receptor, relaxin family peptide receptor 1 (RXFP1). The lead compound of this series, ML290, was selected based on its effects on the expression of fibrosis-related genes in primary human stellate cells. RNA sequencing analysis of TGF-β1-activated LX-2 cells showed that ML290 treatment primarily affected extracellular matrix remodeling and cytokine signaling, with expression profiles indicating an antifibrotic effect of ML290. ML290 treatment in human liver organoids with LPS-induced fibrotic phenotype resulted in a significant reduction of type I collagen. The pharmacokinetics of ML290 in mice demonstrated its high stability , as evidenced by the sustained concentrations of compound in the liver. In mice expressing human gene treated with carbon tetrachloride, ML290 significantly reduced collagen content, α-smooth muscle actin expression, and cell proliferation around portal ducts. In conclusion, ML290 demonstrated antifibrotic effects in liver fibrosis.-Kaftanovskaya, E. M., Ng, H. H., Soula, M., Rivas, B., Myhr, C., Ho, B. A., Cervantes, B. A., Shupe, T. D., Devarasetty, M., Hu, X., Xu, X., Patnaik, S., Wilson, K. J., Barnaeva, E., Ferrer, M., Southall, N. T., Marugan, J. J., Bishop, C. E., Agoulnik, I. U., Agoulnik, A. I. Therapeutic effects of a small molecule agonist of the relaxin receptor ML290 in liver fibrosis.
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http://dx.doi.org/10.1096/fj.201901046RDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988856PMC
November 2019

A randomized, proof-of-concept clinical trial on repurposing chlorcyclizine for the treatment of chronic hepatitis C.

Antiviral Res 2019 03 31;163:149-155. Epub 2019 Jan 31.

Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address:

Background & Aims: Chlorcyclizine HCl (CCZ) is a piperazine-class antihistamine with anti-hepatitis C virus (HCV) activity in vitro and in vivo. In a first-in-humans study for HCV, we evaluated the antiviral effects and safety of CCZ±ribavirin (RBV), characterized pharmacokinetic (PK) and viral kinetic (VK) patterns, and provide insights into CCZs mode of action against HCV.

Methods: Chronic HCV patients were randomized to CCZ (75 mg twice daily) or CCZ+weight-based RBV (1000/1200 mg daily) for 28 days. Therapy started with a loading dose of CCZ 150 mg ± RBV. Serial assessments of safety, liver tests, PK and VK markers were obtained.

Results: 24 HCV patients were treated; 54% male, median age 56 years, median HCV RNA 6.30 log IU/ml, without baseline differences between groups. At the end of therapy, subjects treated with CCZ monotherapy did not show any significant or sustained reduction in viremia (p = 0.69), whereas 7/12 (58%) subjects treated with CCZ+RBV had a >3-fold decline in HCV RNA. Subjects who responded demonstrated monophasic (n = 2), biphasic (n = 2) and triphasic (n = 3) VK responses. Contrary to historical RBV monotherapy response, CCZ+RBV demonstrated a continued viral decline suggesting a possible synergistic effect of CCZ+RBV. Mathematical modeling predicts a median effectiveness of CCZ+RBV in blocking viral production (ε) of 59% (Interquartile range, IQR: 50%) and blocking infection (η) of 78% (IQR: 23%). Adverse events (AEs) were mild-moderate without treatment discontinuations for AEs.

Conclusions: In this human pilot study, CCZ demonstrated some anti-HCV effects, mostly in combination with RBV. More potent CCZ derivatives with optimal PK features may be more suitable for future therapeutic development. ClinicalTrials.gov number: NCT02118012.
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http://dx.doi.org/10.1016/j.antiviral.2019.01.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402797PMC
March 2019

Deconstructing the Translational Tower of Babel.

Clin Transl Sci 2019 03 9;12(2):85. Epub 2018 Nov 9.

National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA.

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http://dx.doi.org/10.1111/cts.12595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440561PMC
March 2019

Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance.

Oncogene 2018 07 17;37(29):3981-3997. Epub 2018 Apr 17.

Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.

Antineoplastic platinum agents are used in first-line treatment of ovarian cancer, but treatment failure frequently results from platinum drug resistance. Emerging observations suggest a role of reactive oxygen species (ROS) in the resistance of cancer drugs including platinum drugs. However, the molecular link between ROS and cellular survival pathway is poorly understood. Using quantitative high-throughput combinational screen (qHTCS) and genomic sequencing, we show that in platinum-resistant ovarian cancer elevated ROS levels sustain high level of IL-11 by stimulating FRA1-mediated IL-11 expression and increased IL-11 causes resistance to platinum drugs by constitutively activating JAK2-STAT5 via an autocrine mechanism. Inhibition of JAK2 by LY2784544 or IL-11 by anti-IL-11 antibody overcomes the platinum resistance in vitro or in vivo. Significantly, clinic studies also confirm the activated IL-11-JAK2 pathway in platinum-resistant ovarian cancer patients, which highly correlates with poor prognosis. These findings not only identify a novel ROS-IL-11-JAK2-mediated platinum resistance mechanism but also provide a new strategy for using LY2784544- or IL-11-mediated immunotherapy to treat platinum-resistant ovarian cancer.
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http://dx.doi.org/10.1038/s41388-018-0238-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054535PMC
July 2018

Up-regulation of lysosomal TRPML1 channels is essential for lysosomal adaptation to nutrient starvation.

Proc Natl Acad Sci U S A 2015 Mar 2;112(11):E1373-81. Epub 2015 Mar 2.

Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, MI 48109; and

Upon nutrient starvation, autophagy digests unwanted cellular components to generate catabolites that are required for housekeeping biosynthesis processes. A complete execution of autophagy demands an enhancement in lysosome function and biogenesis to match the increase in autophagosome formation. Here, we report that mucolipin-1 (also known as TRPML1 or ML1), a Ca(2+) channel in the lysosome that regulates many aspects of lysosomal trafficking, plays a central role in this quality-control process. By using Ca(2+) imaging and whole-lysosome patch clamping, lysosomal Ca(2+) release and ML1 currents were detected within hours of nutrient starvation and were potently up-regulated. In contrast, lysosomal Na(+)-selective currents were not up-regulated. Inhibition of mammalian target of rapamycin (mTOR) or activation of transcription factor EB (TFEB) mimicked a starvation effect in fed cells. The starvation effect also included an increase in lysosomal proteostasis and enhanced clearance of lysosomal storage, including cholesterol accumulation in Niemann-Pick disease type C (NPC) cells. However, this effect was not observed when ML1 was pharmacologically inhibited or genetically deleted. Furthermore, overexpression of ML1 mimicked the starvation effect. Hence, lysosomal adaptation to environmental cues such as nutrient levels requires mTOR/TFEB-dependent, lysosome-to-nucleus regulation of lysosomal ML1 channels and Ca(2+) signaling.
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http://dx.doi.org/10.1073/pnas.1419669112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4371935PMC
March 2015

Discovery and characterization of a G protein-biased agonist that inhibits β-arrestin recruitment to the D2 dopamine receptor.

Mol Pharmacol 2014 Jul 22;86(1):96-105. Epub 2014 Apr 22.

Molecular Neuropharmacology Section, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, Bethesda, Maryland (R.B.F., L.S.C., A.E.M., B.N.M., T.B.D., J.L.C., A.P., J.A.M., D.R.S.); National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland (J.X., X.H., A.E.D., S.T., M.B.-G., E.B., M.F., N.T.S., J.J.M.); Cellular, Molecular, Developmental Biology & Biophysics Program, Johns Hopkins University, Baltimore, Maryland (L.S.C.); Center for Molecular Recognition and Departments of Psychiatry and Pharmacology, Columbia University College of Physicians and Surgeons, and Division of Molecular Therapeutics, New York State Psychiatric Institute, New York, New York (Y.H., L.D., J.A.J.); Schrödinger Inc., New York, New York (T.B.); and Department of Physiology and Biophysics and Institute for Computational Biomedicine, Weill Medical College of Cornell University, New York, New York (L.S.).

A high-throughput screening campaign was conducted to interrogate a 380,000+ small-molecule library for novel D2 dopamine receptor modulators using a calcium mobilization assay. Active agonist compounds from the primary screen were examined for orthogonal D2 dopamine receptor signaling activities including cAMP modulation and β-arrestin recruitment. Although the majority of the subsequently confirmed hits activated all signaling pathways tested, several compounds showed a diminished ability to stimulate β-arrestin recruitment. One such compound (MLS1547; 5-chloro-7-[(4-pyridin-2-ylpiperazin-1-yl)methyl]quinolin-8-ol) is a highly efficacious agonist at D2 receptor-mediated G protein-linked signaling, but does not recruit β-arrestin as demonstrated using two different assays. This compound does, however, antagonize dopamine-stimulated β-arrestin recruitment to the D2 receptor. In an effort to investigate the chemical scaffold of MLS1547 further, we characterized a set of 24 analogs of MLS1547 with respect to their ability to inhibit cAMP accumulation or stimulate β-arrestin recruitment. A number of the analogs were similar to MLS1547 in that they displayed agonist activity for inhibiting cAMP accumulation, but did not stimulate β-arrestin recruitment (i.e., they were highly biased). In contrast, other analogs displayed various degrees of G protein signaling bias. These results provided the basis to use pharmacophore modeling and molecular docking analyses to build a preliminary structure-activity relationship of the functionally selective properties of this series of compounds. In summary, we have identified and characterized a novel G protein-biased agonist of the D2 dopamine receptor and identified structural features that may contribute to its biased signaling properties.
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http://dx.doi.org/10.1124/mol.113.090563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4054005PMC
July 2014

Small-molecule agonists for the thyrotropin receptor stimulate thyroid function in human thyrocytes and mice.

Proc Natl Acad Sci U S A 2009 Jul 10;106(30):12471-6. Epub 2009 Jul 10.

Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

Seven-transmembrane-spanning receptors (7TMRs) are prominent drug targets. However, small-molecule ligands for 7-transmembrane-spanning receptors for which the natural ligands are large, heterodimeric glycoprotein hormones, like thyroid-stimulating hormone (TSH; thyrotropin), have only recently been reported, and none are approved for human use. We have used quantitative high-throughput screening to identify a small-molecule TSH receptor (TSHR) agonist that was modified to produce a second agonist with increased potency. We show that these agonists are highly selective for human TSHR versus other glycoprotein hormone receptors and interact with the receptor's serpentine domain. A binding pocket within the transmembrane domain was defined by docking into a TSHR homology model and was supported by site-directed mutagenesis. In primary cultures of human thyrocytes, both TSH and the agonists increase mRNA levels for thyroglobulin, thyroperoxidase, sodium iodide symporter, and deiodinase type 2, and deiodinase type 2 enzyme activity. Moreover, oral administration of the agonist stimulated thyroid function in mice, resulting in increased serum thyroxine and thyroidal radioiodide uptake. Thus, we discovered a small molecule that activates human TSHR in vitro, is orally active in mice, and could be a lead for development of drugs to use in place of recombinant human TSH in patients with thyroid cancer.
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http://dx.doi.org/10.1073/pnas.0904506106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708975PMC
July 2009

A basis for reduced chemical library inhibition of firefly luciferase obtained from directed evolution.

J Med Chem 2009 Mar;52(5):1450-8

NIH Chemical Genomics Center, National Institutes of Health, Bethesda, Maryland 20892-3370, USA.

We measured the "druggability" of the ATP-dependent luciferase derived from the firefly Photuris pennsylvanica that was optimized using directed evolution (Ultra-Glo, Promega). Quantitative high-throughput screening (qHTS) was used to determine IC(50)s of 198899 samples against a formulation of Ultra-Glo luciferase (Kinase-Glo). We found that only 0.1% of the Kinase-Glo inhibitors showed an IC(50) < 10 microM compared to 0.9% found from a previous qHTS against the firefly luciferase from Photinus pyralis (lucPpy). Further, the maximum affinity identified in the lucPpy qHTS was 50 nM, while for Kinase-Glo this value increased to 600 nM. Compounds with interactions stretching outside the luciferin binding pocket were largely lost with Ultra-Glo luciferase. Therefore, Ultra-Glo luciferase will show less compound interference when used as an ATP sensor compared to lucPpy. This study demonstrates the power of large-scale quantitative analysis of structure-activity relationships (>100K compounds) in addressing important questions such as a target's druggability.
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http://dx.doi.org/10.1021/jm8014525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430137PMC
March 2009

Characterization of chemical libraries for luciferase inhibitory activity.

J Med Chem 2008 Apr 26;51(8):2372-86. Epub 2008 Mar 26.

NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-3370, USA.

To aid in the interpretation of high-throughput screening (HTS) results derived from luciferase-based assays, we used quantitative HTS, an approach that defines the concentration-response behavior of each library sample, to profile the ATP-dependent luciferase from Photinus pyralis against more than 70,000 samples. We found that approximately 3% of the library was active, containing only compounds with inhibitory concentration-responses, of which 681 (0.9%) exhibited IC 50 < 10 microM. Representative compounds were shown to inhibit purified P. pyralis as well as several commercial luciferase-based detection reagents but were found to be largely inactive against Renilla reniformis luciferase. Light attenuation by the samples was also examined and found to be more prominent in the blue-shifted bioluminescence produced by R. reniformis luciferase than in the bioluminescence produced by P. pyralis luciferase. We describe the structure-activity relationship of the luciferase inhibitors and discuss the use of this data in the interpretation of HTS results and configuration of luciferase-based assays.
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http://dx.doi.org/10.1021/jm701302vDOI Listing
April 2008

Fluorescence spectroscopic profiling of compound libraries.

J Med Chem 2008 Apr 26;51(8):2363-71. Epub 2008 Mar 26.

NIH Chemical Genomics Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892-3370, USA.

Chromo/fluorophoric properties often accompany the heterocyclic scaffolds and impurities that comprise libraries used for high-throughput screening (HTS). These properties affect assay outputs obtained with optical detection, thus complicating analysis and leading to false positives and negatives. Here, we report the fluorescence profile of more than 70,000 samples across spectral regions commonly utilized in HTS. The quantitative HTS paradigm was utilized to test each sample at seven or more concentrations over a 4-log range in 1,536-well format. Raw fluorescence was compared with fluorophore standards to compute a normalized response as a function of concentration and spectral region. More than 5% of library members were brighter than the equivalent of 10 nM 4-methyl umbelliferone, a common UV-active probe. Red-shifting the spectral window by as little as 100 nm was accompanied by a dramatic decrease in autofluorescence. Native compound fluorescence, fluorescent impurities, novel fluorescent compounds, and the utilization of fluorescence profiling data are discussed.
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http://dx.doi.org/10.1021/jm701301mDOI Listing
April 2008

Kinase patent space visualization using chemical replacements.

J Med Chem 2006 Mar;49(6):2103-9

Informatics Department, Celera Genomics, 45 West Gude Drive, Rockville, Maryland 20850, USA.

Here we present a methodology for characterizing the structure of patented chemical space. This approach identifies those chemical replacements that can connect sets of exemplified compounds in individual patents. Chemists can then search these replacements to help them discover the architecture within their patent space of interest. To demonstrate the utility of such an approach, we characterize a set of kinase inhibitors from patents and literature and find that many companies' patents can be understood to be straightforward modifications of competitors' patents. By reapplying these same chemical themes to other related compound series, novel, biologically active compounds can be discovered.
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http://dx.doi.org/10.1021/jm051201mDOI Listing
March 2006

Potential of mean force between two hydrophobic solutes in water.

Biophys Chem 2002 Dec;101-102:295-307

Graduate Group in Biophysics, University of California at San Francisco, San Francisco, CA 94143-1204, USA.

We study the potential of mean force between two nonpolar solutes in the Mercedes Benz model of water. Using NPT Monte Carlo simulations, we find that the solute size determines the relative preference of two solute molecules to come into contact ('contact minimum') or to be separated by a single layer of water ('solvent-separated minimum'). Larger solutes more strongly prefer the contacting state, while smaller solutes have more tendency to become solvent-separated, particularly in cold water. The thermal driving forces oscillate with solute separation. Contacts are stabilized by entropy, whereas solvent-separated solute pairing is stabilized by enthalpy. The free energy of interaction for small solutes is well-approximated by scaled-particle theory.
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http://dx.doi.org/10.1016/s0301-4622(02)00167-9DOI Listing
December 2002

How ions affect the structure of water.

J Am Chem Soc 2002 Oct;124(41):12302-11

Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia.

We model ion solvation in water. We use the MB model of water, a simple two-dimensional statistical mechanical model in which waters are represented as Lennard-Jones disks having Gaussian hydrogen-bonding arms. We introduce a charge dipole into MB waters. We perform (NPT) Monte Carlo simulations to explore how water molecules are organized around ions and around nonpolar solutes in salt solutions. The model gives good qualitative agreement with experiments, including Jones-Dole viscosity B coefficients, Samoilov and Hirata ion hydration activation energies, ion solvation thermodynamics, and Setschenow coefficients for Hofmeister series ions, which describe the salt concentration dependence of the solubilities of hydrophobic solutes. The two main ideas captured here are (1) that charge densities govern the interactions of ions with water, and (2) that a balance of forces determines water structure: electrostatics (water's dipole interacting with ions) and hydrogen bonding (water interacting with neighboring waters). Small ions (kosmotropes) have high charge densities so they cause strong electrostatic ordering of nearby waters, breaking hydrogen bonds. In contrast, large ions (chaotropes) have low charge densities, and surrounding water molecules are largely hydrogen bonded.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1513647PMC
http://dx.doi.org/10.1021/ja026014hDOI Listing
October 2002