Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8.
The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC(50) values ranging from 12.16 to 83.96 microM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (K(I) values ranging from 0.62 to 16.1 microM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.
Saraiva
Juliana
J
Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.
Siqueira
Claudia Meirelles
CM
de Paula da Silva
Carlos Henrique Tomich
CH
Barreto da Silva
Vinicius
V
Tudella
Valeria Gomes
VG
Silva
Rosangela
R
Andrade E Silva
Marcio Luis
ML
Dorta
Daniel Junqueira
DJ
Bastos
Jairo Kenupp
JK
Uyemura
Sergio Akira
SA
de Albuquerque
Sergio
S
Curti
Carlos
C
D000818:Animals; D019069:Cell Respiration / Q000187:drug effects; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D017705:Lignans / Q000737:chemistry* / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011487:Protein Conformation; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism
D017705:Lignans; D009097:Multienzyme Complexes; D021122:Protein Subunits; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I; C433065:cubebin