| Peptic Ulcer is a common and frequently encountered disease with a morbidity rate of 15% in the whole population. This disease is mainly caused by the over-secretion of gastric acid. Therefore, drugs with activities in inhibiting the secretion of gastric acid are a constant hotspot in new drug development.During the study on new synthetically routes of benzimidazole compounds, we found that a group of N-aryl isothiourea compounds have similar three-dimensional structure with them. So we suspected that they might have similar activities. Isothiourea compounds have pesticidal, antibacterial activities, and also can inhibit the activity of nitric oxide synthase. Yet, we didn't find any reports about their activity on inhibiting the secretion of gastric acid.In our former study, we have synthesized dozens of benzimidazole compounds and these compounds have been shown a certain activity on inhibiting the secretion of gastric acid. Some of them are even more effective than proton pump inhibitor-pantoprazole sodium. Based on the results of the former study, we designed and synthesized 81 N-aryl isothiourea compounds and justified their structures with NMR and MS methods. After searching in the related reference, we found 75 of them are unreported. In the inhibiting the gastric acid secretion of guinea pig stomach mucous membrane study, we choosed pantoprazole magnesium as a positive drug and found that 27 of the target compounds have a higher or equal activity compared with the positive drug. At the same time, we found that substitute on pyridine have effect on the acting time and its binding ability with the stomach cells.Nowadays, Computer-Aided Drug Design (CADD) has become an important method in new drug research and development. In order to find out the relationship between the inhibiting activity and structure of isothiourea compounds and design high-efficient, low-toxic and high-selectively compounds and shorten the process from new compounds to new drug, CoMFA and CoMSIA methods were introduced tostudy the relationship between the structure and activity of the compounds. We also analyzed the effects on the CoMFA results made by the selection of grid space, methods of caculating electric charges and probe atoms in CoMFA field. Then, concerned the factors and using AOS, a CoMFA model with strong predictive ability was obtained and the model could provide directions in structures optimized. However, using CoMSIA didn't get a proper model. But after bringing hydrophobic field based steric and electrostatic fields, the model then have a certain predictive ability, which indicates that hydrophobic effects have some effects on the activity of the compounds.H+, K+-ATPase is an important protein related to secretion of gastric acid and it mainly controls the last step of the secretion of gastric acid. Therefore, to inhibit H+. K+-ATP enzyme could achieve the purpose on inhibiting secretion of gastric acid. But until now, we didn't know the three-dimensional structure yet. By using homology modeling method, its three-dimensional structure model was constructed. The active mode of the irreversible H+, K+-ATP enzyme inhibitor was simulated based on the three-dimensional structure and the active pocket reported, and found the disulfide bond energy was rising followed the razoles' activity. At the same time, the long acyclic substitutes in pyridine of lansoprazole and rabeprazole push the side chains of cysteine to make the sulfinyl more exposured. It can be presumed that the energy of the sulfide bond and the substitutes in phenyl were related with the activity.Based on the above results, we simulated the active mode of the reversible H+, K+-ATP enzyme inhibitor and found: the conformation of the SCH28080 like a bow integrates in the pocket surround by Glu795, Glu822, Glu936, Phe126 and Cys813. The phenyl of SCH28080 interacted with the phenyl of Phe126, and the polar part interacted with negatively charged residues.All of above are the theoretical basis of the structure-based reasonable drug designi...
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