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Extending the small-molecule similarity principle to all levels of biology with the Chemical Checker (vol 34, pg 591, 2020)

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NATURE BIOTECHNOLOGY 2020年第9期38卷 1098-1098页

作者： Duran-Frigola, Miquel Pauls, Eduardo Guitart-Pla, Oriol Bertoni, Martino Alcalde, Victor Amat, David Juan-Blanco, Teresa Aloy, Patrick Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) The Barcelona Institute of Science and Technology Barcelona Spain Institució Catalana de Recerca i Estudis Avançats (ICREA) Barcelona Spain

Small molecules are usually compared by their chemical structure, but there is no unified analytic framework for representing and comparing their biological activity. We present the Chemical Checker (CC), which provides processed, harmonized and integrated bioactivity data on ~800,000 small molecules. The CC divides data into five levels of increasing complexity, from the chemical properties of compounds to their clinical outcomes. In between, it includes targets, off-targets, networks and cell-level information, such as omics data, growth inhibition and morphology. Bioactivity data are expressed in a vector format, extending the concept of chemical similarity to similarity between bioactivity signatures. We show how CC signatures can aid drug discovery tasks, including target identification and library characterization. We also demonstrate the discovery of compounds that reverse and mimic biological signatures of disease models and genetic perturbations in cases that could not be addressed using chemical information alone. Overall, the CC signatures facilitate the conversion of bioactivity data to a format that is readily amenable to machine learning methods.

关键词： Chemical biology Chemical genetics Chemical libraries Cheminformatics Drug discovery

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Drug repositioning beyond the low-hanging fruits

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Current Opinion in Systems biology 2017年 3卷 95-102页

作者： Duran-Frigola, Miquel Mateo, Lidia Aloy, Patrick Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) The Barcelona Institute of Science and Technology Barcelona Catalonia Spain Institució Catalana de Recerca i Estudis Avançats (ICREA) Barcelona Catalonia Spain

Approved drug molecules have undergone safety and efficacy examination, succeeding in a series of screens with typically high attrition rates. Today, these privileged entities are well characterized: the amount of data that has been collected for drugs - from mechanisms of action to all sorts of molecular signatures - is far beyond that of the rest of compounds available to researchers. As biomedicine is going omics, and with the advent of systems biology, drug molecules constitute a standard toolbox to probe and challenge disease models, which are increasing in complexity and start to account for patient variability. Here, we discuss why drug repositioning is not only an economically attractive idea, but also one of the most realistic settings for systems pharmacology. © 2017 Elsevier Ltd.

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Cover Image, Volume 9, Issue 6

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WIREs computational Molecular Science 2019年第6期9卷

作者： Miquel Duran-Frigola Adrià Fernández-Torras Martino Bertoni Patrick Aloy Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute of Science and Technology Barcelona Spain Patrick Aloy Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute of Science and Technology Barcelona Catalonia Spain. Institució Catalana de Recerca i Estudis Avançats (ICREA) Barcelona Spain Miquel Duran-Frigola Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) Barcelona Institute of Science and Technology Barcelona Catalonia Spain.

The cover image is based on the Advanced Review Formatting biological big data for modern machine learning in drug discovery , by Miquel Duran-Frigola, Adrià Fernández-Torras, Martino Bertoni and Patrick Alo...

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Publisher Correction: Extending the small-molecule similarity principle to all levels of biology with the Chemical Checker

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Nature biotechnology 2020年第9期38卷 1098页

作者： Miquel Duran-Frigola Eduardo Pauls Oriol Guitart-Pla Martino Bertoni Víctor Alcalde David Amat Teresa Juan-Blanco Patrick Aloy Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) The Barcelona Institute of Science and Technology Barcelona Spain. miquel.duran@***. Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) The Barcelona Institute of Science and Technology Barcelona Spain. Joint IRB-BSC-CRG Program in Computational Biology Institute for Research in Biomedicine (IRB Barcelona) The Barcelona Institute of Science and Technology Barcelona Spain. patrick.aloy@***. Institució Catalana de Recerca i Estudis Avançats (ICREA) Barcelona Spain. patrick.aloy@***.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Real‐Time Atomistic Description of DNA Unfolding†

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Angewandte Chemie 2010年第28期122卷

作者： Alberto Perez Modesto Orozco Joint IRB–BSC Research Program in Computational Biology Institute for Research in Biomedicine (IRB) Josep Samitier 1–5 Barcelona 08028 (Spain) http://mmb.pcb.ub.es Barcelona Supercomputing Centre (BSC) Jordi Girona 29 Barcelona 08034 (Spain)

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Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2

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Cancer Treatment and research Communications 2018年 15卷 21-31页

作者： Galván-Femenía, Iván Guindo, Marta Duran, Xavier Calabuig-Fariñas, Sílvia Mercader, Josep Maria Ramirez, Jose Luis Rosell, Rafael Torrents, David Carreras, Anna Kohno, Takashi Jantus-Lewintre, Eloisa Camps, Carlos Perucho, Manuel Sumoy, Lauro Yokota, Jun de Cid, Rafael Genomes For life-GCAT Lab. Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain Barcelona Supercomputing Center (BSC-CNS) Joint BSC-CRG-IRB Research Program in Computational Biology Carrer de Jordi Girona 29-31 Barcelona 08034 Spain Department of Medical Oncology Hospital General Universitario de Valencia Avenida Tres Cruces 2 València 46014 Spain Molecular Oncology Laboratory Fundación Hospital General Universitario de Valencia Avda. Tres Cruces s/n València 46014 Spain Department of Pathology Universitat de València Av. de Blasco Ibáñez 13 València 46010 Spain Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain ICREA Catalan Institution for Research and Advanced Studies Spain Division of Genome Biology National Cancer Center Research Institute 5-1-1 Tsukiji Chuo-ku Tokyo 104-0045 Japan Molecular Oncology Laboratory Fundación Hospital General Universitario de València Avda. Tres Cruces s/n València 46014 Spain Department of Biotechnology Universitat Politècnica de València Camí de Vera s/n València 46022 Spain Department of Medicine Universitat de València Av. de Blasco Ibáñez 13 València 46010 Spain Genomics and Bioinformatics. Program of Predictive and Personalized Medicine of Cancer (PMPPC) Institute for Health Science Research Germans Trias i Pujol (IGTP) Can Ruti Biomedical Campus Crta de Can Ruti Camí de les Escoles S/N Badalona 08916 Barcelona Spain Programs in Metabolism and Medical & Population Genetics Broad Institute of Harvard and MIT Cambridge Massachusetts United States Diabetes Unit and Center for Human Genetic Research Massachusetts General Hospital Boston Massachuse

Objective: The aim of the study was to investigate the relationship between germline variations as a prognosis biomarker in patients with advanced Non-Small-Cell-Lung-Cancer (NSCLC) subjected to first-line platinum-based treatment. Materials and Methods: We carried out a two-stage genome-wide-association study in non-small-cell lung cancer patients with platinum-based chemotherapy in an exploratory sample of 181 NSCLC patients from Caucasian origin, followed by a validation on 356 NSCLC patients from the same ancestry (Valencia, Spain). Results: We identified germline variants in SMYD2 as a prognostic factor for survival in patients with advanced NSCLC receiving chemotherapy. SMYD2 alleles are associated to a decreased overall survival and with a reduced Time to Progression. In addition, enrichment pathway analysis identified 361 variants in 40 genes to be involved in poorer outcome in advanced-stage NSCLC patients. Conclusion: Germline SMYD2 alleles are associated with bad clinical outcome of first-line platinum-based treatment in advanced NSCLC patients. This result supports the role of SMYD2 in the carcinogenic process, and might be used as prognostic signature directing patient stratification and the choice of therapy. A two-Stage Genome wide association study in Caucasian population reveals germline genetic variation in SMYD2 associated to progression disease in first-line platinum-based treatment in advanced NSCLC patients. SMYD2 profiling might have prognostic / predictive value directing choice of therapy and enlighten current knowledge on pathways involved in human carcinogenesis as well in resistance to chemotherapy. © 2018 The Authors

关键词： Advanced stage Genome-Wide-Association Studies Lung cancer NSCLC Prognostic factors

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Can A Denaturant Stabilize DNA? Pyridine Reverses DNA Denaturation in Acidic pH

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Angewandte Chemie 2015年第36期127卷

作者： Guillem Portella Montserrat Terrazas Núria Villegas Carlos González Modesto Orozco Institute for Research in Biomedicine (IRB Barcelona) Joint BSC‐IRB Research Program in Computational Biology Barcelona (Spain) Department of Chemistry University of Cambridge Cambridge CB2 1EW (UK) Barcelona Supercomputing Center Barcelona (Spain) Instituto de Química Física Rocasolano CSIC Madrid (Spain) Department of Biochemistry and Molecular Biology University of Barcelona (Spain)

The stability of DNA is highly dependent on the properties of the surrounding solvent, such as ionic strength, pH, and the presence of denaturants and osmolytes. Addition of pyridine is known to unfold DNA by replacing π–π stacking interactions between bases, stabilizing conformations in which the nucleotides are solvent exposed. We show here experimental and theoretical evidences that pyridine can change its role and in fact stabilize the DNA under acidic conditions. NMR spectroscopy and MD simulations demonstrate that the reversal in the denaturing role of pyridine is specific, and is related to its character as pseudo groove binder. The present study sheds light on the nature of DNA stability and on the relationship between DNA and solvent, with clear biotechnological implications.

关键词： Denaturierungsmittel Ionen‐DNA‐Wechselwirkungen Moleküldynamik NMR‐Spektroskopie Nukleinsäuredynamik

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Structure and Dynamics of Oligonucleotides in the Gas Phase†

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Angewandte Chemie 2014年第2期127卷

作者： Annalisa Arcella Jens Dreyer Emiliano Ippoliti Ivan Ivani Guillem Portella Valérie Gabelica Paolo Carloni Modesto Orozco Institute for Research in Biomedicine (IRB Barcelona) Joint BSC‐CRG‐IRB Program on Computational Biology Barcelona (Spain) Computational Biophysics German Research School for Simulation Sciences and Institute for Advanced Simulation IAS‐5 Computational Biomedicine Forschungszentrum Jülich (Germany) Mass Spectrometry Laboratory Department of Chemistry University of Liège (Belgium) Univ. Bordeaux IECB ARNA Laboratory 33600 Pessac (France) Inserm U869 ARNA Laboratory 33000 Bordeaux (France) Institute for Neuroscience and Medicine INM‐9 Computational Biomedicine Forschungszentrum Jülich (Germany) Department of Biochemistry and Molecular Biology University of Barcelona (Spain)

By combining ion‐mobility mass spectrometry experiments with sub‐millisecond classical and ab initio molecular dynamics we fully characterized, for the first time, the dynamic ensemble of a model nucleic acid in the gas phase under electrospray ionization conditions. The studied oligonucleotide unfolds upon vaporization, loses memory of the solution structure, and explores true gas‐phase conformational space. Contrary to our original expectations, the oligonucleotide shows very rich dynamics in three different timescales (multi‐picosecond, nanosecond, and sub‐millisecond). The shorter timescale dynamics has a quantum mechanical nature and leads to changes in the covalent structure, whereas the other two are of classical origin. Overall, this study suggests that a re‐evaluation on our view of the physics of nucleic acids upon vaporization is needed.

关键词： Ab‐initio‐Rechnungen DNA Gasphase Massenspektrometrie Moleküldynamik

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Multiple Routes to Characterize the Folding of a Small DNA Hairpin†

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Angewandte Chemie 2010年第42期122卷

作者： Guillem Portella Modesto Orozco Joint IRB‐BSC Research Program in Computational Biology Institute for Research in Biomedicine (IRB) Josep Samitier 1‐5 Barcelona 08028 (Spain) Barcelona Supercomputing Centre (BSC) Jordi Girona 29 Barcelona 08034 (Spain) Departament de Bioquímica i Biología Molecular Facultat de Biología Universitat de Barcelona Avgda Diagonal 645 Barcelona 08028 (Spain) National Institute of Bioinformatics Parc Científic de Barcelona Josep Samitier 1–5 Barcelona 08028 (Spain)

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Backbone FCH⋅⋅⋅O Hydrogen Bonds in 2′F‐Substituted Nucleic Acids†

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Angewandte Chemie 2013年第46期125卷

作者： Nerea Martin‐Pintado Glen F. Deleavey Guillem Portella Ramón Campos‐Olivas Modesto Orozco Masad J. Damha Carlos González Instituto de Química Física “Rocasolano” CSIC Serrano 119 28006 Madrid (Spain) Department of Chemistry McGill University 801 Sherbrooke St. West Montreal QC H3A 0B8 (Canada) Joint IRB‐BSC program on Computational Biology Institute for Research in Biomedicine Barcelona Supercomputing Center and Department of Biochemistry University of Barcelona Baldir i Reixac 10–12 08028 Barcelona (Spain) Spectroscopy and NMR Unit Spanish National Cancer Center (CNIO) C/Melchor Fernández Almagro 3 28029 Madrid (Spain)

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