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Virtual Screening and Experimental Characterization of Histone Deacetylase (HDAC) Inhibitors
Virtual Screening and Experimental Characterization of Histone Deacetylase (HDAC) Inhibitors
Mutations in many genes have been associated with Amyotrophic Lateral Sclerosis (ALS). This fatal neurodegenerative disease has no cure. Among the genes most prominently studied, mutations in the protein FUS can lead to the disease. We have recently linked alterations in histone acetylation levels to yeast models of FUS dysfunction. These models are characterized by cell death in the context of FUS overexpression. In effort to rescue the cells, the cells were treated with a known human HDAC inhibitor, Trichostatin A(TSA). The results showed signs of cell rescue, however, our objective was to predict an inhibitor that would show more significant results. Here we analyzed the interactions between human HDAC inhibitor and yeast HDAC. We compared protein structures of human and yeast HDACs. We also predicted the docking of different known human HDAC inhibitors to the yeast HDAC. The primary binding site was identical between human and yeast HDAC, but the secondary area of binding site showed different residues. The resulting molecule chosen for future testing was Panobinostat. It showed a good docking score in human and yeast HDAC.
Mutations in many genes have been associated with Amyotrophic Lateral Sclerosis (ALS). This fatal neurodegenerative disease has no cure. Among the genes most prominently studied, mutations in the protein FUS can lead to the disease. We have recently linked alterations in histone acetylation levels to yeast models of FUS dysfunction. These models are characterized by cell death in the context of FUS overexpression. In effort to rescue the cells, the cells were treated with a known human HDAC inhibitor, Trichostatin A(TSA). The results showed signs of cell rescue, however, our objective was to predict an inhibitor that would show more significant results. Here we analyzed the interactions between human HDAC inhibitor and yeast HDAC. We compared protein structures of human and yeast HDACs. We also predicted the docking of different known human HDAC inhibitors to the yeast HDAC. The primary binding site was identical between human and yeast HDAC, but the secondary area of binding site showed different residues. The resulting molecule chosen for future testing was Panobinostat. It showed a good docking score in human and yeast HDAC.
Elizaveta Son Poster for Student Showcase 1_2020.pdfHere we analyzed the structures of human and yeast HDAC, HDAC6 and Rpd3 respectively. Primarily, we are focusing on the binding site of each protein. We are looking for any differences or similarities between the two. The binding sites seem to be almost identical, though there is an unmatched asparate residue on Rpd3. This could explain the difference in TSA efficiency.
We also analyzed how different inhibitors docked to the proteins, especially Rpd3. The objective was to find an inhibitor with a better docking score than TSA. A docking score of higher magnitude represents a better match.
Elizaveta Son Poster for Student Showcase 1_2020.pdfHere we analyzed the structures of human and yeast HDAC, HDAC6 and Rpd3 respectively. Primarily, we are focusing on the binding site of each protein. We are looking for any differences or similarities between the two. The binding sites seem to be almost identical, though there is an unmatched asparate residue on Rpd3. This could explain the difference in TSA efficiency.
We also analyzed how different inhibitors docked to the proteins, especially Rpd3. The objective was to find an inhibitor with a better docking score than TSA. A docking score of higher magnitude represents a better match.
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