title: Structure-based design and biological profile of (E)-N-(4-Nitrobenzylidene)-2-naphthohydrazide, a novel small molecule inhibitor of IκB kinase-β.
abstract: In this study, we describe the rational design, molecular modeling and pharmacological profile of a novel IKK-β inhibitor (E)-N-(4-nitrobenzylidene)-2-naphthohydrazide (LASSBio-1524). The design based on the IKK-β active site, and a privileged structure template yielded a novel IKK-β inhibitor scaffold with significant selectivity over IKK-α and CHK2, as assessed by an in vitro kinase assay. For a better understanding of the structural requirements of IKK-β inhibition, molecular dynamics simulations of LASSBio-1524 (3) were performed. The NAH derivative LASSBio-1524 (3), was able to suppress arachidonic acid-induced edema formation in a dose-dependent manner, demonstrating an in vivo anti-inflammatory effect. The molecular architecture of this novel, low-molecular weight IKK-β inhibitor is encouraging for further lead optimization toward the development of innovative anti-inflammatory drug candidates.
authors.affiliation: Laboratório de Avaliação e Síntese de Substâncias Bioativas, Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902 Rio de Janeiro, Brazil.
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Avila
authors.forename: Alexandra B
authors.initials: AB
authors.lastname: Lopes
authors.forename: Arlan S
authors.initials: AS
authors.lastname: Gonçalves
authors.forename: Leandro L
authors.initials: LL
authors.lastname: da Silva
authors.forename: Nelilma C
authors.initials: NC
authors.lastname: Romeiro
authors.forename: Ana Luisa P
authors.initials: AL
authors.lastname: Miranda
authors.forename: Carlos M R
authors.initials: CM
authors.lastname: Sant'Anna
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001597:Benzylidene Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D002460:Cell Line; D015195:Drug Design; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D005260:Female; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D008297:Male; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D008970:Molecular Weight; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000893:Anti-Inflammatory Agents; D001597:Benzylidene Compounds; D006835:Hydrazones; D008024:Ligands; C558589:N-(4-nitrobenzylidene)-2-naphthohydrazide; D047428:Protein Kinase Inhibitors; D051550:I-kappa B Kinase