Rational design of inhibitors against TAR DNA-binding protein 43 (TDP-43) to prevent neurodegenerative disorders

TAR DNA-binding protein (TDP-43) is primarily found in the nucleus and has a vital function in the processing of RNA/DNA and the control of genes. Mutations in this protein are linked to neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and inhibiting the mutated protein will help in preventing these diseases. Due to the complex and flexible nature of the protein the complete 3D structure of this protein is complicated to obtain. In our work, we have used computational strategies like structure elucidation techniques to profit the DNA-bound three-dimensional structure of this protein. In addition, molecular docking simulations were performed to identify inhibitors capable of binding to the mutated RRM1 protein, thus preventing the mutated protein functioning. Our hypothesis is that that docking ligands binds to the portions of the protein that bind to DNA and prevent the DNA binding to the mutate protein. According to our research, we have identified five chemical compounds that have a high affinity for RRM1 protein. All the ligands bind to the DNA interacting domain of the RRM1 protein. In addition, we have also predicted the complete three- dimensional configuration of DNA bound TDP-43 protein complex and according to our understanding, this is the first time the complex 3D structure has been reported. Based on the elucidated structure and electrostatic surface potential the negatively charged DNA binds only to the positively charged RRM1 do- main of the TDP-43 protein. The current investigation will help in developing novel therapeutics against neurodegenerative diseases.