Computational studies on structural modifications for the inhibition of matrix metalloproteinase activities by luteolin

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 [...]