Mechanisms of interaction between luteolin and the catalytic zinc ion in matrix metalloproteinases: a computational study

Many experimental studies have found that flavonoids including luteolin can inhibit the activities of matrix metalloproteinases (MMPs), but the related theoretical studies are rather lacking. In this paper, we perform PM6 quantum chemistry calculations together with modeling of ligand‐water exchange reactions to investigate the mechanisms of interaction between luteolin and catalytic zinc ion in MMPs. The calculations show that the electron transfer from the luteolin molecule to the catalytic zinc ion in MMPs occurs when the catalytic zinc ion coordinates with the O atoms of substituent groups at various positions of A, B, and C rings of luteolin molecule. It is found that the more the number of the electron transfer from one coordinating O atom of substituent groups of luteolin molecule to the catalytic zinc ion, the stronger the coordinating ability between them. We further find that comparing with the O atoms of hydroxy groups at 5‐, 7‐, 3′‐, and 4′‐positions of luteolin molecule, the coordinating ability for the O atom of carbonyl group at its 4‐position with the catalytic zinc ion is the strongest, which indicates that when luteolin inhibits MMPs activity, the catalytic zinc ion should coordinate with the carbonyl group at 4‐position of luteolin molecule, rather than the hydroxy groups at its other positions, in agreement with the relevant experimental results reported in previous literature. This paper may be helpful for designing the new MMPs inhibitors having higher biological activities by carrying out the structural modifications of luteolin molecule. Copyright © 2012 John Wiley & Sons, Ltd.