Investigations on the mechanisms of interactions between matrix metalloproteinase 9 and its flavonoid inhibitors using a combination of molecular docking, hybrid quantum mechanical/molecular mechanical calculations, and molecular dynamics simulations

: 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 [...]