Autor segons l'article: Sala E, Guasch L, Iwaszkiewicz J, Mulero M, Salvadó MJ, Pinent M, Zoete V, Grosdidier A, Garcia-Vallvé S, Michielin O, Pujadas G
Departament: Bioquímica i Biotecnologia
Autor/s de la URV: Garcia Vallve, Santiago / Mulero Abellán, Miguel / Pinent Armengol, Montserrat / Pujadas Anguiano, Gerard / Salvadó Rovira, Maria Josepa
Paraules clau: Procianidinas
Resum: 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.
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Accès a la llicència d'ús: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 19326203
Adreça de correu electrònic de l'autor: mariajosepa.salvado@urv.cat gerard.pujadas@urv.cat santi.garcia-vallve@urv.cat montserrat.pinent@urv.cat miquel.mulero@urv.cat
Identificador de l'autor: 0000-0003-3883-3326 0000-0003-2598-8089 0000-0002-0348-7497 0000-0003-3550-5378
Data d'alta del registre: 2023-02-26
Versió de l'article dipositat: info:eu-repo/semantics/publishedVersion
Enllaç font original: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0016903
Referència a l'article segons font original: Plos One. 6 (2): e16903-
Referència de l'ítem segons les normes 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
URL Document de llicència: https://repositori.urv.cat/ca/proteccio-de-dades/
DOI de l'article: 10.1371/journal.pone.0016903
Entitat: Universitat Rovira i Virgili
Any de publicació de la revista: 2011
Tipus de publicació: Journal Publications
Repositori URV