Research Center Basica

Tres Cantos, Spain

Research Center Basica

Tres Cantos, Spain
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Singh S.B.,Merck And Co. | Goetz M.A.,Merck And Co. | Smith S.K.,Merck And Co. | Zink D.L.,Merck And Co. | And 14 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

Emergence of bacterial resistance has eroded the effectiveness of many life saving antibiotics leading to an urgent need for new chemical classes of antibacterial agents. We have applied a Staphylococcus aureus fitness test strategy to natural products screening to meet this challenge. In this paper we report the discovery of kibdelomycin A, a demethylated congener of kibdelomycin, the representative of a novel class of antibiotics produced by a new strain of Kibdelosporangium. Kibdelomycin A is a potent inhibitor of DNA gyrase and topoisomerase IV, inhibits DNA synthesis and shows whole cell antibiotic activity, albeit, less potently than kibdelomycin. Kibdelomycin C-33 acetate and tetrahydro-bisdechloro derivatives of kibdelomycin were prepared which helped define a basic SAR of the family. © 2012 Elsevier Ltd. All rights reserved.


Espinosa J.F.,Research Center Basica
Current Topics in Medicinal Chemistry | Year: 2011

In situ structural characterization of organic compounds attached to solid supports can be achieved by highresolution magic angle spinning NMR (HRMAS NMR), a technique that provides solution-like spectra for resin-bound molecules. This review outlines the principles of the technique, the influence of the solid support on data quality, and NMR experiments that are useful for obtaining valuable information. The review describes, with multiple examples mainly from the last 7 years, how HRMAS NMR has been applied to monitor solid-phase reactions, elucidate reaction products and quantify compound loading on a solid support. Other applications, such as conformational analysis of immobilized compounds and investigation of molecular interactions with compounds in solution, are also discussed. © 2011 Bentham Science Publishers Ltd.


Phillips J.W.,Merck And Co. | Phillips J.W.,Allen Institute for Brain Science | Goetz M.A.,Merck And Co. | Smith S.K.,Merck And Co. | And 20 more authors.
Chemistry and Biology | Year: 2011

Bacterial resistance to known therapeutics has led to an urgent need for new chemical classes of antibacterial agents. To address this we have applied a Staphylococcus aureus fitness test strategy to natural products screening. Here we report the discovery of kibdelomycin, a novel class of antibiotics produced by a new member of the genus Kibdelosporangium. Kibdelomycin exhibits broad-spectrum, gram-positive antibacterial activity and is a potent inhibitor of DNA synthesis. We demonstrate through chemical genetic fitness test profiling and biochemical enzyme assays that kibdelomycin is a structurally new class of bacterial type II topoisomerase inhibitor preferentially inhibiting the ATPase activity of DNA gyrase and topoisomerase IV. Kibdelomycin is thus the first truly novel bacterial type II topoisomerase inhibitor with potent antibacterial activity discovered from natural product sources in more than six decades. © 2011 Elsevier Ltd All rights reserved.


Theobald A.J.,Glaxosmithkline | Caballero I.,Biological Reagents and Assay Development | Caballero I.,Research Center Basica | Coma I.,Screening and Compound Profiling | And 9 more authors.
Biochemistry | Year: 2012

Plasmodium falciparum is the most prevalent and deadly species of the human malaria parasites, and thioredoxin reductase (TrxR) is an enzyme involved in the redox response to oxidative stress. Essential for P. falciparum survival, the enzyme has been highlighted as a promising target for novel antimalarial drugs. Here we report the discovery and characterization of seven molecules from an antimalarial set of 13533 compounds through single-target TrxR biochemical screens. We have produced high-purity, full-length, recombinant native enzyme from four Plasmodium species, and thioredoxin substrates from P. falciparum and Rattus norvegicus. The enzymes were screened using a unique, high-throughput, in vitro native substrate assay, and we have observed selectivity between the Plasmodium species and the mammalian form of the enzyme. This has indicated differences in their biomolecular profiles and has provided valuable insights into the biochemical mechanisms of action of compounds with proven antimalarial activity. © 2012 American Chemical Society.


Vela L.,Research Center Basica | Caballero I.,Research Center Basica | Fang L.,GSK China RandD Company Ltd | Liu Q.,GSK China RandD Company Ltd | And 3 more authors.
Journal of Biomolecular Screening | Year: 2015

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that involves activation of T cells, microglia, and astrocytes. There is a clear unmet medical need for MS, as current therapies reduce the relapse rate, but are unable to prevent the neurological deterioration. Leukemia inhibitory factor (LIF) is a proinflammatory cytokine that can also positively modulate the immune response, by inducing the inhibition of myelin-reactive TH17 differentiation, and by promoting oligodendrocyte-mediated myelination. The aim of this project was to find central nervous system (CNS)-permeable and orally available small molecules that upregulate production of endogenous LIF. We describe here the development of a phenotypic assay and screening of 1.7 million compounds to identify LIF enhancers using U87 MG cells. Five chemically tractable series of compounds and a few singletons were selected for further progression. Some of them were also active in a different LIF-expressing cell line and in primary rat astrocytes. Although further studies would be required to deconvolute the targets involved in LIF induction and to confirm activity of hits in more disease-relevant assays, our results have demonstrated the potential of the phenotypic approach to identify specific and chemically tractable small molecules that trigger the production of LIF in relevant cell lines. © Society for Laboratory Automation and Screening.


PubMed | GSK China R&D Company Ltd and Research Center Basica
Type: Journal Article | Journal: Journal of biomolecular screening | Year: 2016

Multiple sclerosis (MS) is an autoimmune neurodegenerative disease that involves activation of T cells, microglia, and astrocytes. There is a clear unmet medical need for MS, as current therapies reduce the relapse rate, but are unable to prevent the neurological deterioration. Leukemia inhibitory factor (LIF) is a proinflammatory cytokine that can also positively modulate the immune response, by inducing the inhibition of myelin-reactive TH17 differentiation, and by promoting oligodendrocyte-mediated myelination. The aim of this project was to find central nervous system (CNS)-permeable and orally available small molecules that upregulate production of endogenous LIF. We describe here the development of a phenotypic assay and screening of 1.7 million compounds to identify LIF enhancers using U87 MG cells. Five chemically tractable series of compounds and a few singletons were selected for further progression. Some of them were also active in a different LIF-expressing cell line and in primary rat astrocytes. Although further studies would be required to deconvolute the targets involved in LIF induction and to confirm activity of hits in more disease-relevant assays, our results have demonstrated the potential of the phenotypic approach to identify specific and chemically tractable small molecules that trigger the production of LIF in relevant cell lines.


Colmenarejo G.,Research Center Basica
Journal of Chemical Information and Modeling | Year: 2016

The triage of compounds at the single-concentration screening phase of high-throughput screening (HTS) requires multiobjective optimization in order to achieve the best selection of hits, both in terms of potency and physicochemical properties, for a given number of compounds to test. In this regard, ligand efficiency indexes, well established as guides for hit prioritization in the dose-response phase of HTS, are less studied in the single-concentration phase. In the present work the use of ligand efficiency indexes in the prioritization of compounds in single-concentration is investigated. Formulas for deriving them from single-concentration screening data are provided. The statistical association between the single-concentration and dose-response ligand efficiency indexes is evaluated with a wide historical data set including multiple screens of different target classes and screening technologies. The results show Pearson's correlation coefficients r above 0.9 for compounds with dose-response curves, and areas under the curve (AUC) of receiver operating characteristic (ROC) curves above 0.85 after including compounds with no dose-response curves. This good statistical association contains the contribution of both the physicochemical parameter(s) in the ligand efficiency indexes, as well as the biological activity, as demonstrated by permutation tests. The "cost/benefit" of using different thresholds of single-concentration ligand efficiency indexes in rescuing different numbers of efficient compounds is systematically investigated, and cost/benefit curves are provided. Approximate thresholds are proposed for the different ligand efficiency parameters that results in large percentages of efficient compounds rescued while attempting to reduce the cost of compounds to test in dose-response mode. Finally, a practical example of implementation of these indexes that considers clustering of compounds is described, where the rescue of efficient compounds is higher and with a much lower cost than a typical response-driven selection. © 2016 American Chemical Society.


Xu D.,Merck Frosst Center for Therapeutic Research | Ondeyka J.,Merck And Co. | Harris G.H.,Merck And Co. | Zink D.,Merck And Co. | And 9 more authors.
Journal of Natural Products | Year: 2011

In a whole-cell mechanism of action (MOA)-based screening strategy for discovery of antifungal agents, Candida albicans was used, followed by testing of active extracts in the C. albicans fitness test (CaFT), which provides insight into the mechanism of action. A fermentation extract of an undescribed species of Metulocladosporiella that inhibited proteasome activity in a C. albicans fitness test was identified. The chemical genomic profile of the extract contained hypersensitivity of heterozygous deletion strains (strains that had one of the genes of the diploid genes knocked down) of genes represented by multiple subunits of the 25S proteasome. Two structurally related peptide aldehydes, named fellutamides C and D, were isolated from the extract. Fellutamides were active against C. albicans and Aspergillus fumigatus with MICs ranging from 4 to 16 μg/mL and against fungal proteasome (IC 50 0.2 μg/mL). Both compounds showed proteasome activity against human tumor cell lines, potently inhibiting the growth of PC-3 prostate carcinoma cells, but not A549 lung carcinoma cells. In PC-3 cells compound treatment produced a G2M cell cycle block and induced apoptosis. Preliminary SAR studies indicated that the aldehyde group is critical for the antifungal activity and that the two hydroxy groups are quantitatively important for potency. © 2011 The American Chemical Society and American Society of Pharmacognosy.


PubMed | Research Center Basica
Type: Journal Article | Journal: Current topics in medicinal chemistry | Year: 2011

In situ structural characterization of organic compounds attached to solid supports can be achieved by high-resolution magic angle spinning NMR (HRMAS NMR), a technique that provides solution-like spectra for resin-bound molecules. This review outlines the principles of the technique, the influence of the solid support on data quality, and NMR experiments that are useful for obtaining valuable information. The review describes, with multiple examples mainly from the last 7 years, how HRMAS NMR has been applied to monitor solid-phase reactions, elucidate reaction products and quantify compound loading on a solid support. Other applications, such as conformational analysis of immobilized compounds and investigation of molecular interactions with compounds in solution, are also discussed.


PubMed | Research Center Basica
Type: Journal Article | Journal: Journal of chemical information and modeling | Year: 2016

The triage of compounds at the single-concentration screening phase of high-throughput screening (HTS) requires multiobjective optimization in order to achieve the best selection of hits, both in terms of potency and physicochemical properties, for a given number of compounds to test. In this regard, ligand efficiency indexes, well established as guides for hit prioritization in the dose-response phase of HTS, are less studied in the single-concentration phase. In the present work the use of ligand efficiency indexes in the prioritization of compounds in single-concentration is investigated. Formulas for deriving them from single-concentration screening data are provided. The statistical association between the single-concentration and dose-response ligand efficiency indexes is evaluated with a wide historical data set including multiple screens of different target classes and screening technologies. The results show Pearsons correlation coefficients r above 0.9 for compounds with dose-response curves, and areas under the curve (AUC) of receiver operating characteristic (ROC) curves above 0.85 after including compounds with no dose-response curves. This good statistical association contains the contribution of both the physicochemical parameter(s) in the ligand efficiency indexes, as well as the biological activity, as demonstrated by permutation tests. The cost/benefit of using different thresholds of single-concentration ligand efficiency indexes in rescuing different numbers of efficient compounds is systematically investigated, and cost/benefit curves are provided. Approximate thresholds are proposed for the different ligand efficiency parameters that results in large percentages of efficient compounds rescued while attempting to reduce the cost of compounds to test in dose-response mode. Finally, a practical example of implementation of these indexes that considers clustering of compounds is described, where the rescue of efficient compounds is higher and with a much lower cost than a typical response-driven selection.

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