Author, as appears in the article.: Sala, Esther; Guasch, Laura; Iwaszkiewicz, Justyna; Mulero, Miquel; Salvado, Maria-Josepa; Pinent, Montserrat; Zoete, Vincent; Grosdidier, Aurelien; Garcia-Vallve, Santiago; Michielin, Olivier; Pujadas, Gerard
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: miquel.mulero@urv.cat; montserrat.pinent@urv.cat; santi.garcia-vallve@urv.cat; gerard.pujadas@urv.cat
Record's date: 2025-02-08
Paper version: info:eu-repo/semantics/publishedVersion
Link to the original source: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016903
Licence document URL: https://repositori.urv.cat/ca/proteccio-de-dades/
Paper original source: Plos One. 6 (2): e16903-
APA: Sala, Esther; Guasch, Laura; Iwaszkiewicz, Justyna; Mulero, Miquel; Salvado, Maria-Josepa; Pinent, Montserrat; Zoete, Vincent; Grosdidier, Aurelien; 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
Article's DOI: 10.1371/journal.pone.0016903
Entity: Universitat Rovira i Virgili
Journal publication year: 2011
Publication Type: Journal Publications
Repositori URV