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: Many experimental studies have found that flavonoids can inhibit the activities of matrix metalloproteinases (MMPs), but the relevant mechanisms are still unclear. In this paper, the interaction mechanisms of MMP-9 with its five flavonoid inhibitors are investigated using a combination of molecular docking, hybrid quantum mechanical and molecular mechanical (QM/MM) calculations, and molecular dynamics simulations. The molecular dynamics simulation results show a good linear correlation between the calculated binding free energies of QM/MM-Poisson-Boltzmann surface area (PBSA) and the experimental -log([EC.sub.50]) regarding the studied five flavonoids on MMP-9 inhibition in explicit solvent. It is found that compared with the MM-PBSA method, the QM/MM-PBSA method can obviously improve the accuracy for the calculated binding free energies. The predicted binding modes of the five flavonoid-MMP-9 complexes reveal that the different hydrogen bond networks can form besides producing the Zn-O coordination bonds, which can reasonably explain previous experimental results. The agreement between our calculated results and the previous experimental facts indicates that the force field parameters used here are effective and reliable for investigating the systems of flavonoid--MMP-9 interactions, and thus, these simulations and analyses could be reproduced for the other related systems involving protein--ligand interactions. This paper maybe helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules. Key words: flavonoid, MMP-9, interaction mechanism, hybrid QM/MM, molecular dynamics simulation. De nombreuses etudes experimentales ont montre que les flavonoides pouvaient inhiber l'activite des metalloproteases matricielles (MMP), mais les mecanismes de cette inhibition demeurent obscurs. Dans le present article, les mecanismes d'interaction entre la MMP-9 et ses inhibiteurs sont etudies en combinant l'amarrage moleculaire, les methodes de calcul hybrides de mecanique quantique et mecanique moleculaire (MQ/MM) et des simulations de dynamique moleculaire. Les resultats de ces dernieres montrent une bonne correlation lineaire entre les energies libres de liaison calculees de la methode QM/MM-Poisson-Boltzmann surface area (QM/MM-PBSA) et la valeur experimentale de -log([EC.sub.50]) en ce qui concerne l'inhibition de l'activite de la MMP-9 par les cinq flavonoides etudies dans un solvant explicite. Il a ete constate, en comparaison de la methode MM-PBSA, que la methode QM/MM-PBSA pouvait ameliorer de fa^on remarquable la precision du calcul des energies libres de liaison. Les predictions des modes de liaison des cinq complexes flavonoide-MMP-9 revelent que differents reseaux de liaisons hydrogenes peuvent se former en plus de creer des liaisons de coordination Zn-O, ce qui permet d'expliquer raisonnablement les precedents resultats experimentaux. La concordance entre les resultats que nous avons calcules et les precedentes observations experimentales montre que les parametres de champ de force utilises ici sont fiables et efficaces pour etudier les interactions des systemes flavonoide--MMP-9 et que ces simulations et analyses pourraient donc etre reproduites dans le cadre d'autres systemes du meme type impliquant des interactions proteine--ligand. La presente publication pourrait s'averer utile pour concevoir les nouveaux inhibiteurs de la MMP-9 a l'activite biologique plus elevee en modifiant la structure des molecules de flavonoides. [Traduit par la Redaction] Mots-cles: flavonoide, MMP-9, mecanisme d'interaction, methode hybride QM/MM, simulation de dynamique moleculaire., Introduction Matrix metalloproteinases (MMPs) comprise a family of zinc proteolytic enzymes that are well known for their ability to degrade the extracellular matrix (ECM) and take part in both normal [...]

Many experimental studies have previously found that flavonoids including luteolin can inhibit the activities of matrix metalloproteinases (MMPs), but the related theoretical studies are rather lacking. In this paper, based on our recently obtained interaction mechanisms between luteolin and the catalytic zinc ion in MMPs (see J. Phys. Org. Chem. 2012,25,1306), we perform PM6 quantum chemistry calculations together with modeling of ligand-water exchange reactions to investigate the relevant structural modifications for the inhibition of MMP activities by luteolin. The calculations indicate that among the possible modified positions of A, B, and C rings of the luteolin molecule, 5, 7, 2=,3=, and 4= should be the five suitable modified positions, and the several usual substituent groups that have stronger electron-donating abilities should be the suitable substituent groups. We further find that with the increasing number of these substituent groups, the biological activities for the modified luteolin molecules on MMP inhibition can be obviously improved. Our calculated results are in agreement with previous relevant experimental results. This paper gives a new approach for designing the new MMP inhibitors having higher biological activities by carrying out the structural modifications of the luteolin molecule. Key words: luteolin, matrix metalloproteinases, structural modifications, PM6, free energy. Alors que de nombreuses etudes experimentales ont indique anterieurement que les flavonoides, y compris la luteoline, peuvent inhiber l'activite des metalloproteases matricielles (MMP), les etudes theoriques connexes sont rares. Dans le present article, fonde sur les mecanismes d'interaction entre la luteoline et l'ion zinc catalytique present dans les MMP que nous avons decouverts recemment (voir J. Phys. Org. Chem. 2012, 25,1306), nous procedons a des calculs de chimie quantique par la methode PM6, ainsi qu'a la modelisation des reactions d'echange ligand-eau afin d'etudier les modifications structurales pertinentes pour l'inhibition de l'activite des MMP par la luteoline. Selon les calculs, parmi les positions modifiees possibles des noyaux A, B et C de la molecule de luteoline, les cinq positions modifiees appropriees devraient etre 5, 7, 2=,3=et 4=, et parmi les groupements substituants habituels, les groupements substituants appropries devraient etre ceux qui sont les plus aptes a donner des electrons. Nous constatons en outre que l'augmentation du nombre de ces substituants peut ameliorer manifestement l'activite biologique d'inhibition des MMP des molecules modifiees de luteoline. Les resultats de nos calculs concordent avec les resultats experimentaux anterieurs pertinents. Le present article decrit une nouvelle approche en vue de concevoir de nouveaux inhibiteurs des MMP possedant une activite biologique accrue qui consiste a modifier structuralement la molecule de luteoline. [Traduit par la Redaction] Mots-cles: luteoline, metalloproteases matricielles, modifications structurales, PM6, energie libre., Introduction Matrix metalloproteinases (MMPs) comprise a family of zinc proteolytic enzymes that are well known for their ability to degrade the extracellular matrix (ECM) and take part in both normal [...]

This research focused on a novel 7-azaisoindigo derivative [namely N(1)-(n-butyl)-7-azaisoindigo, 7-AI-b], and investigated its molecular antitumor mechanism by exploring the means of cell death and the effects on mitochondrial function. 7-AI-b inhibited cancer cell proliferation in a dose- and time-dependent way. The morphological and nuclei changes in H(2) B-GFP-labeled HeLa cells were observed using a live cell system. The results suggested that cell death induced by 7-AI-b is closely related to apoptosis. 7-AI-b induced release of cytochrome C from mitochondria to cytosol and activation of caspase-3, showing that the apoptosis is mediated by the mitochondrial pathway. Furthermore, our data indicated that 7-AI-b triggers apoptosis through reactive oxygen species (ROS): cellular ROS levels were increased after 3 h exposure of 7-AI-b, which was reversed by the ROS scavenger N-acetyl-L-cysteine. As a consequence, 7-AI-b-mediated cell death, mitochondrial transmembrane potential collapse and ATP level were partly blocked by N-acetyl-L-cysteine. Further study showed that 7-AI-b could induce mitochondrial dysfunction: collapse of the mitochondrial transmembrane potential and reduction of intracellular ATP level. In summary, the novel synthesized 7-AI-b was demonstrated to be effective in killing cancer cells via an ROS-promoted and mitochondria- and caspase-dependent apoptotic pathway., (Copyright © 2010 John Wiley & Sons, Ltd.)