With density functional theory（DFT） and molecular mechanics method, the catalytic mechanism of silent information regulator（sirtuins） has been investigated. The calculations support the SN2-1ike reaction of the initial step of the catalysis, and are consistent with experiment results. We further explored the second step of the catalysis and proposed that this step took place in a concerted reaction. In addition, the side chain of Phenylalanine33 may help to shield the glycosidic bond from water and be in a position to protect the developing oxacabenium transition state from hydrolysis. Our results of the calculations support this hypothesis that the phenylalanine33 plays a critical role in the sirtuins biology function.
Drugs SPD-304（6,7-dimethyl-3-{[methyl-（2-{methyl-[1-（3-trifluoromethyl-phenyl）-1H-indol-3-ylme thyl]-amino}-ethyl）-amino]-methyl}-chromen-4-one） and zafirlukast contain a common structural element of 3-substituted indole moiety which closely relates to a dehydrogenated reaction catalyzed by cytochrome P450s（CYPs）. It was reported that the dehydrogenation can produce a reactive electrophilic intermediate which cause toxicities and inactivate CYPs. Drug L-745,870（3-{[4-（4-chlorophenyl）piperazin-1-yl]-methyl}-1H-pyrrolo 2,3-β-pyridine） might have similar effect since it contains the same structural element. We used molecular docking approach combined with molecular dynamics（MD） simulation to model three-dimensional（3D） complex structures of SPD-304, zafirlukast and L-745,870 into CYP3A4, respectively. The results show that these three drugs can stably bind into the active site and the 3-methylene carbons of the drugs keep a reasonable reactive distance from the heme iron. The complex structure of SPD-304-CYP3A4 is in agreement with experimental data. For zafirlukast, the calcu lation results indicate that 3-methylene carbon might be the dehydrogenation reaction site. Docking model of L-745,870-CYP3A4 shows a potential possibility of L-745,870 dehydrogenated by CYP3A4 at 3-methylene carbon which is in agreement with experiment in vivo. In addition, residues in the phenylalanine cluster as well as S119 and R212 play a critical role in the ligands binding based on our calculations. The docking models could provide some clues to understand the metabolic mechanism of the drugs by CYP3A4.
MENG Xuan-yu, LI Zhuo, NIU Rui-juan, ZHANG Hong-xing and ZHENG Qing-chuan State Key Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, Jilin University, Changchun 130021, P. R. China
Glutathione transferases（GSTs） play an important role in the detoxification of xenobiotic/endobiotic toxic compounds. The α-, π-, and/l-classes of cytosolic GSTs have been studied extensively, while Gtt2 from Saccharo- myces cerevisiae, a novel atypical GST, is still poorly understood. In the present study, we investigated the gluta- thione（GSH） activation mechanism of Gtt2 using the density functional theory（DFT） with the hybrid functional B3LYP. The computational results show that a water molecule could assist a proton transfer between the GSH thiol and the N atom of His133. The energy barrier of proton transfer is 46.0 kJ/mol. The GSH activation mechanism and the characteristics of active site are different from those of classic cytosolic GSTs.
LI XueWU Yun-jianLI ZhuoCHU Wen-tingZHANG Hong-xingZHENG Qing-chuan
