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Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1.

ABSTRACT: MTH1 can hydrolyze oxidized nucleotides and is required for cancer survival. The IC50 values were 0.8?nM for TH287 with a methyl substitution, 5.0?nM for TH588 with a cyclopropyl substitution, and 2.1??M for TH650 with an oxetanyl substitution. Thus, it is very significant to understand inhibitory mechanisms of these structurally similar compounds against MTH1 and influences of the substituent on the bioactivities. Our MD researches indicate that TH287 maintains significant hydrogen bonds with Asn33 and Asp119, stabilizes the binding site, and induces MTH1 adopt a closed motion, leading to a high inhibitory activity. When bound with TH588, the binding site can be partially stabilized and take a semi-closed state, which is because the cyclopropyl group in TH588 has larger steric hindrance than a methyl group in TH287. So TH588 has a slightly reduced inhibitory activity compared to TH287. TH650 induces greater conformation fluctuations than TH588 and the binding site adopts an opening state, which is caused by the large bulk of oxetanyl group and the interference of solvent on the oxetanyl substituent, leading to the lowest inhibitory activity. Thus, the inhibitory activity follows a TH287?>?TH588?>?TH650 trend, which well matches with the experimental finding.

SUBMITTER: Wang M

PROVIDER: S-EPMC5225434 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1.

Wang Mian M Zhou Shuilian S Chen Qing Q Wang Lisheng L Liang Zhiqun Z Wang Jianyi J

Scientific reports 20170111

MTH1 can hydrolyze oxidized nucleotides and is required for cancer survival. The IC<sub>50</sub> values were 0.8 nM for TH287 with a methyl substitution, 5.0 nM for TH588 with a cyclopropyl substitution, and 2.1 μM for TH650 with an oxetanyl substitution. Thus, it is very significant to understand inhibitory mechanisms of these structurally similar compounds against MTH1 and influences of the substituent on the bioactivities. Our MD researches indicate that TH287 maintains significant hydrogen b ...[more]

PMID: 28074893

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Project description:Background/Aim: Essential oils of sunflower receptacles (SEOs) have antibacterial and antioxidant potential. However, the differences of biological activities from the different varieties of sunflowers have not been studied till now. The purpose of this study was to compare the differences of chemical compounds, antioxidant activities, and inhibitory activities against xanthine oxidase (XO) of SEOs from the three varieties of sunflowers including LD5009, SH363, and S606. Methods: SEOs were extracted by using the optimal extraction conditions selected by response surface methodology (RSM). Chemical compounds of SEOs were identified from the three varieties of sunflowers by gas chromatography-mass spectrometry (GC-MS). Antioxidant activities of SEOs were detected by 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), 2,2-diphenyl-1-picrylhydrazyl (DPPH), and iron ion reduction ability. Inhibitory activities of SEOs against XO were measured by using UV spectrophotometer. XO inhibitors were selected from the main chemical compounds of SEOs by the high-throughput selections and molecular simulation docking. Results: The extraction yields of SEOs from LD5009, SH363, and S606 were 0.176, 0.319, and 0.580%, respectively. A total of 101 chemical compounds of SEOs were identified from the three varieties of sunflowers. In addition, the results of inhibitory activities against XO showed that SEOs can reduce uric acid significantly. Eupatoriochromene may be the most important chemical compounds of SEOs for reducing uric acid. The results of antioxidant activities and inhibitory activities against XO showed that SEOs of LD5009 had the strongest antioxidant and XO inhibitory activities. The Pearson correlation coefficient (r > 0.95) showed that γ-terpinene, (E)-citral, and L-Bornyl acetate were highly correlated with the antioxidant activities and XO inhibitory ability. Conclusion: SEOs had antioxidant activities and XO inhibitory ability. It would provide more scientific information for utilization and selection of varieties of sunflowers, which would increase the food quality of sunflowers and incomes of farmers.

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Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1.

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Understanding the molecular mechanism for the differential inhibitory activities of compounds against MTH1.

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