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(EC50) 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 may be helpful for designing the new MMP-9 inhibitors having higher biological activities by carrying out the structural modifications of flavonoid molecules.
AIM:To observe the effects of mouse nerve growth factor (NGF), rat recombinant brain derived neurotrophic factor (rm-BDNF) and recombinant human neurotrophin-3 (rh-NT-3) on the gastrointestinal motility and the migrating myoelectric complex (MMC) in rat. METHODS:A randomized, double-blinded, placebo-controlled experiment was performed. 5-7 days after we chronically implanted four or five bipolar silver electrodes on the stomach, duodenum, jejunum and colon, 21 experimental rats were coded and divided into 3 groups and injected NGF, rm-BDNF, rh-NT-3 or placebo respectively via tail vein at a dose of 20 µg·kg -1 . The gastrointestinal myoelectrical activity was recorded 2 hours before and after the test substance infusions in these consciously fasting rats. RESULTS:The neurotrophins-induced pattern of activity was characterized by enhanced spiking activity of different amplitudes at all recording sites, especially in the colon. In the gastric antrum and intestine, only rh-NT-3 had increased effects on the demographic characteristics of electrical activities (P<0.05), but did not affect the intervals of MMCs. In the colon, all the three kinds of neurotrophins could significantly increase the frequency, amplitude and duration levels of spike bursts, and also rh-NT-3 could prolong the intervals of MMC in the transverse colon (25±11 min vs 19±6 min, P<0.05). In the distal colon rh-NT-3 could evoke phase III-like activity and disrupt the MMC pattern, which was replaced by a continuously long spike bursts (LSB) and irregular spike activity (ISA) for 48±6 min. CONCLUSION:Exogenous neurotrophic factors can stimulate gut myoelectric activities in rats.
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