Articles producció científica> Bioquímica i Biotecnologia

Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays

  • Identification data

    Identifier: imarina:5124355
    Authors:
    Sala E, Guasch L, Iwaszkiewicz J, Mulero M, Salvadó MJ, Pinent M, Zoete V, Grosdidier A, Garcia-Vallvé S, Michielin O, Pujadas G
    Abstract:
    Background: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. Methodology/Principal Findings: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. Conclusions/Significance: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing n
  • Others:

    Author, as appears in the article.: Sala E, Guasch L, Iwaszkiewicz J, Mulero M, Salvadó MJ, Pinent M, Zoete V, Grosdidier A, Garcia-Vallvé S, Michielin O, Pujadas G
    Department: Bioquímica i Biotecnologia
    URV's Author/s: Garcia Vallve, Santiago / Mulero Abellán, Miguel / Pinent Armengol, Montserrat / Pujadas Anguiano, Gerard / Salvadó Rovira, Maria Josepa
    Keywords: Procianidinas
    Abstract: Background: Their large scaffold diversity and properties, such as structural complexity and drug similarity, form the basis of claims that natural products are ideal starting points for drug design and development. Consequently, there has been great interest in determining whether such molecules show biological activity toward protein targets of pharmacological relevance. One target of particular interest is hIKK-2, a serine-threonine protein kinase belonging to the IKK complex that is the primary component responsible for activating NF-κB in response to various inflammatory stimuli. Indeed, this has led to the development of synthetic ATP-competitive inhibitors for hIKK-2. Therefore, the main goals of this study were (a) to use virtual screening to identify potential hIKK-2 inhibitors of natural origin that compete with ATP and (b) to evaluate the reliability of our virtual-screening protocol by experimentally testing the in vitro activity of selected natural-product hits. Methodology/Principal Findings: We thus predicted that 1,061 out of the 89,425 natural products present in the studied database would inhibit hIKK-2 with good ADMET properties. Notably, when these 1,061 molecules were merged with the 98 synthetic hIKK-2 inhibitors used in this study and the resulting set was classified into ten clusters according to chemical similarity, there were three clusters that contained only natural products. Five molecules from these three clusters (for which no anti-inflammatory activity has been previously described) were then selected for in vitro activity testing, in which three out of the five molecules were shown to inhibit hIKK-2. Conclusions/Significance: We demonstrated that our virtual-screening protocol was successful in identifying lead compounds for developing new inhibitors for hIKK-2, a target of great interest in medicinal chemistry. Additionally, all the tools developed during the current study (i.e., the homology model for the hIKK-2 kinase domain and the pharmacophore) will be made available to interested readers upon request. © 2011 Sala et al.
    Thematic Areas: Zootecnia / recursos pesqueiros Sociology Sociología Serviço social Saúde coletiva Química Psychology Psicología Planejamento urbano e regional / demografia Odontología Nutrição Multidisciplinary sciences Multidisciplinary Medicine (miscellaneous) Medicina veterinaria Medicina iii Medicina ii Medicina i Materiais Matemática / probabilidade e estatística Linguística e literatura Letras / linguística Interdisciplinary research in the social sciences Interdisciplinar Human geography and urban studies History & philosophy of science Historia Geografía Geociências General medicine General biochemistry,genetics and molecular biology General agricultural and biological sciences Farmacia Environmental studies Ensino Engenharias iv Engenharias iii Engenharias ii Engenharias i Enfermagem Educação física Educação Economia Direito Demography Comunicação e informação Ciências sociais aplicadas i Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciências ambientais Ciências agrárias i Ciência política e relações internacionais Ciência de alimentos Ciência da computação Biotecnología Biology Biodiversidade Biochemistry, genetics and molecular biology (miscellaneous) Astronomia / física Arquitetura, urbanismo e design Archaeology Antropologia / arqueologia Anthropology Agricultural and biological sciences (miscellaneous) Administração, ciências contábeis e turismo Administração pública e de empresas, ciências contábeis e turismo
    licence for use: https://creativecommons.org/licenses/by/3.0/es/
    ISSN: 19326203
    Author's mail: mariajosepa.salvado@urv.cat gerard.pujadas@urv.cat santi.garcia-vallve@urv.cat montserrat.pinent@urv.cat miquel.mulero@urv.cat
    Author identifier: 0000-0003-3883-3326 0000-0003-2598-8089 0000-0002-0348-7497 0000-0003-3550-5378
    Record's date: 2023-02-26
    Papper version: info:eu-repo/semantics/publishedVersion
    Link to the original source: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016903
    Papper original source: Plos One. 6 (2): e16903-
    APA: Sala E, Guasch L, Iwaszkiewicz J, Mulero M, Salvadó MJ, Pinent M, Zoete V, Grosdidier A, Garcia-Vallvé S, Michielin O, Pujadas G (2011). Identification of Human IKK-2 Inhibitors of Natural Origin (Part I): Modeling of the IKK-2 Kinase Domain, Virtual Screening and Activity Assays. Plos One, 6(2), e16903-. DOI: 10.1371/journal.pone.0016903
    Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
    Article's DOI: 10.1371/journal.pone.0016903
    Entity: Universitat Rovira i Virgili
    Journal publication year: 2011
    Publication Type: Journal Publications
  • Keywords:

    Agricultural and Biological Sciences (Miscellaneous),Biochemistry, Genetics and Molecular Biology (Miscellaneous),Biology,Medicine (Miscellaneous),Multidisciplinary,Multidisciplinary Sciences
    Procianidinas
    Zootecnia / recursos pesqueiros
    Sociology
    Sociología
    Serviço social
    Saúde coletiva
    Química
    Psychology
    Psicología
    Planejamento urbano e regional / demografia
    Odontología
    Nutrição
    Multidisciplinary sciences
    Multidisciplinary
    Medicine (miscellaneous)
    Medicina veterinaria
    Medicina iii
    Medicina ii
    Medicina i
    Materiais
    Matemática / probabilidade e estatística
    Linguística e literatura
    Letras / linguística
    Interdisciplinary research in the social sciences
    Interdisciplinar
    Human geography and urban studies
    History & philosophy of science
    Historia
    Geografía
    Geociências
    General medicine
    General biochemistry,genetics and molecular biology
    General agricultural and biological sciences
    Farmacia
    Environmental studies
    Ensino
    Engenharias iv
    Engenharias iii
    Engenharias ii
    Engenharias i
    Enfermagem
    Educação física
    Educação
    Economia
    Direito
    Demography
    Comunicação e informação
    Ciências sociais aplicadas i
    Ciências biológicas iii
    Ciências biológicas ii
    Ciências biológicas i
    Ciências ambientais
    Ciências agrárias i
    Ciência política e relações internacionais
    Ciência de alimentos
    Ciência da computação
    Biotecnología
    Biology
    Biodiversidade
    Biochemistry, genetics and molecular biology (miscellaneous)
    Astronomia / física
    Arquitetura, urbanismo e design
    Archaeology
    Antropologia / arqueologia
    Anthropology
    Agricultural and biological sciences (miscellaneous)
    Administração, ciências contábeis e turismo
    Administração pública e de empresas, ciências contábeis e turismo
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