Dissertation > Medicine, health > Pharmacy > Drug basic science

Ⅰ.Development of Murine Model for in Vivoassay of Antitrypanosomal Agents Ⅱ.Allosteric Database and Characteristicsanalysis of Allosteric Modulators

Author WangZuo
Tutor ZhouHuChen
School Shanghai Jiaotong University
Course Pharmaceutical Engineering
Keywords Trypanosoma brucei Human African Trypanosomiasis chalcone–benzoxaborole hybrid molecules a murine model Allosteric modulation allosteric database allosteric modulators structural rigidity
Type Master's thesis
Year 2012
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Human African Trypanosomiasis (HAT), also known as African sleeping sickness, is a parasitic disease of humans caused by protozoal parasite Trypanosoma brucei (T. brucei) and transmitted by the tsetse fly. This endemic disease threatens about 36 countries and 60 million people and it is estimated that 50,000 - 70,000 people are currently infected in Africa. At present, only four drugs are in common use for the treatment of HAT. Due to the serious side effect of these drugs, it is urgently need to develop new novel antitrypanosomal agents. In recent years, benzoxaboroles and chalcones were discovered as new drug candidates of HAT. In order to investigate the potential synergistic effect of benzoxaborole and chalcone scaffolds, a series of chalcone-benzoxaborole hybrid molecules were synthesized and their ability to inhibit bloodstream form of T. brucei was evaluated. Furthermore, we successfully cultured T. brucei in vitro, and then a murine model of T. brucei infection was developed and used in this study to evaluate the efficacy against acute infections of 12 chalcone–benzoxaborole hybrid compounds. The result showed that compound 10 gave moderate in vivo efficacy with 20% survival rate. In addition, compound 8 and 11 showed 100% survival rate and complete elimination of T. brucei parasites 30 days after infection. Among the regulation mechanisms of cellular function, allosteric regulation is the most direct, rapid and efficient way. Allosteric modulation boasts several advantages over orthosteric modulation due to the quiescence in the absence of endogenous activity, high selectivity and limited modulation effect, and allosteric modulators are expected to play a more positive role in pharmaceutical research and development. However, an enormous amount of unsystematic allostery information has deterred scientists in allostery field, and under the current experimental condition, some difficulties like low affinity and unknown composition of potential allosteric small-molecules usually obstruct the discovery of allosteric modulators. In the study, we present the AlloSteric Database (ASD) which is the first online database that contains 336 allosteric proteins and 8095 modulators. Afterwards, all allosteric modulators from ASD were analyzed in comparison with various compounds from different databases to unveil the structural and qualitative characteristics of allosteric modulators. The results show that allosteric modulators are generally constructed by higher structural rigidity, in terms of the number of rotatable bonds and rings; containing more hydrophobic scaffolds is another important feature for the allosteric modulators. Based on the analysis, an empirical rule like Lipinski’s―rule of five‖was defined to determine the structural requirements to be an allosteric modulator. It is found that a large proportion of allosteric modulators (80%) can be successfully retrieved by this―allosteric modulator likeness‖filter in comparison with compounds from other databases, which shows good discriminating power in identifying allosteric modulators. Therefore, the study provides deeper insight into chemical properties of allosteric modulators and also shows good potential in the design or optimization of allosteric compounds.

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