Temporal change in the occlusal vertical dimension and its involvement in modulation of jaw movement in bite-reduced animals.

The occlusal vertical dimension (OVD) in guinea pigs is maintained by tooth eruption and grinding. It has been reported that the experimentally raised OVD recovers to the innate OVD within a few days in guinea pigs. However, the mechanisms underlying OVD adjustment are not entirely understood. This study thus aimed to clarify whether the experimentally reduced OVD would recover. Bite-reduced guinea pigs were created by applying bilateral intermaxillary elastics for 10 days. Guinea pigs without elastics were used as a control. The OVD after removal of the elastics in the experimental group was compared with that of the control group. Jaw movement during chewing was also compared between the experimental and control groups. After removal of the elastics, the experimentally reduced OVD did not recover fully and a significant difference was observed between the experimental and control groups for up to 25 days during the recording period. The minimum closed position during chewing was significantly higher in the experimental group than in the control group, whereas the maximum open position was no different between the groups. The present findings indicated that the experimentally reduced OVD could not be fully recovered, suggesting that reduction of the OVD may have limited influence on jaw movement.

Combined QM/MM (ONIOM) and QSAR approach to the study of complex formation of matrix metalloproteinase­9 with a series of biphenylsulfonamides−LERE-QSAR analysis (V).

We previously proposed a novel QSAR (quantitative structure-activity relationship) procedure called LERE (linear expression by representative energy terms)-QSAR involving molecular calculations such as an ab initio fragment molecular orbital ones. In the present work, we applied LERE-QSAR to complex formation of matrix metalloproteinase-9 (MMP-9) with a series of substituted biphenylsulfonamides. The results shows that the overall free-energy change accompanying complex formation is due to predominantly the contribution from the electrostatic interaction with the zinc atom in the active site of MMP-9. Carbonic anhydrase (CA) belongs to the zinc-containing protease family. In contrast to the current case of MMP-9, the overall free-energy change during complex formation of CA with a series of benzenesulfonamides is due to the contributions from the solvation and dissociation free-energy changes, as previously reported. Comparison of the two sets of results indicates quantitative differences in the relative contributions of free-energy components to the overall free-energy change between the two data sets, corresponding with those in the respective classical QSAR equations. The LERE-QSAR procedure was demonstrated to quantitatively reveal differences in the binding mechanisms between the two cases involving similar but different zinc-containing proteins at the electronic and atomic levels.

Correlation analyses on binding affinity of sialic acid analogues and anti-influenza drugs with human neuraminidase using ab initio MO calculations on their complex structures--LERE-QSAR analysis (IV).

We carried out full ab initio fragment molecular orbital (FMO) calculations for complexes comprising human neuraminidase-2 (hNEU2) and sialic acid analogues including anti-influenza drugs zanamivir (Relenza) and oseltamivir (Tamiflu) in order to examine the variation in the observed inhibitory activity toward hNEU2 at the atomic and electronic levels. We recently proposed the LERE (linear expression by representative energy terms)-QSAR (quantitative structure-activity relationship) procedure. LERE-QSAR analysis quantitatively revealed that the complex formation is driven by hydrogen-bonding and electrostatic interaction of hNEU2 with sialic acid analogues. The most potent inhibitory activity, that of zanamivir, is attributable to the strong electrostatic interaction of a positively charged guanidino group in zanamivir with negatively charged amino acid residues in hNEU2. After we confirmed that the variation in the observed inhibitory activity among sialic acid analogues is excellently reproducible with the LERE-QSAR equation, we examined the reason for the remarkable difference between the inhibitory potencies of oseltamivir as to hNEU2 and influenza A virus neuraminidase-1 (N1-NA). Several amino acid residues in close contact with a positively charged amino group in oseltamivir are different between hNEU2 and N1-NA. FMO-IFIE (interfragment interaction energy) analysis showed that the difference in amino acid residues causes a remarkably large difference between the overall interaction energies of oseltamivir with hNEU2 and N1-NA. The current results will be useful for the development of new anti-influenza drugs with high selectivity and without the risk of adverse side effects.