| Summary: | 碩士 === 國立交通大學 === 生物資訊及系統生物研究所 === 102 === Drug repositioning, identifying new indications for an old drug, is able to provide additional therapeutic applications. The cost and time for drug developments are known can be reduced because the properties of old drugs, such as toxicology. It also accelerates new therapeutic strategies into clinical trials. The current approaches of drug repositioning are based on the concepts of similar proteins with similar function or similar compounds with similar pharmacology activity. However, the interactions may be different between similar proteins or similar compounds. Therefore, we introduce the concept of molecular interaction into this research. To identify the potential targets of repositioned drugs, we proposed the concept of “homologous protein-compound complexes” bases on interactions between proteins and compounds. In homologous protein-compound complexes, the proteins bind the same group of compounds are defined as “SimpharmaPro”, compounds bind the same group of proteins are defined as “SimpharmaCom”, and the interactions between SimpharmaPro and SimpharmaCom are defined as “SimpharmaIntact”.
To verify the concept of this research, we collected the FDA-approved drugs with crystal structures and target proteins to construct 134 groups homologous protein-compound complexes, which contains 248 FDA-approved drugs for new uses. There are 145 potential interactions identified and annotated in public database, and 126 among them are with experimental data showing IC50 ≦ 10μM. The accuracy is 86%. To verify our concept, we select 3 potential interactions to confirm by cell toxicity experiments. The first example is dobutamine, a 1 adrenergic stimulator, originally use in the treatments of cardiogenic shock and heart failure. In our research, we predicted that dobutamine potentially targets to 2 adrenergic receptor, which is associated with lung cancer. Furthermore, the IC50 of dobutamine in a lung cancer cell line is 56.7μM. The second example is podofilox, originally use is to treating warts and keratoses. We predicted the podofilox potentially targets to DNA topoisomerase 2-, which is associated with lung cancer. Furthermore, the IC50 of podofilox in a lung cancer cell line is 2.2nM. We believe that the “homologous protein-compound complexes” proposed in this thesis can have the potential for understanding molecular binding mechanisms and giving new clues for drug repositioning for drug development.
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