In silico Analyses of Gene Expression and Protein Structure/Function and Applications in Disease

Analyzing protein structure and function and identifying gene expression levels that vary in health and disease can lead to elucidation of disease mechanisms, drug target discovery and identification of underlying biomarkers. To this end, this dissertation focuses on three areas involving drug development and disease comprehension. In the first part, an RNA-Seq based gene signature for the prediction of breast cancer metastasis was identified and validated to be prognostic for risk assessment and patient stratification. After diagnosis, cancer progression and metastasis play critical roles in patient survival, thus identifying the genes that correlate with cancer progression and metastasis is essential for selecting effective treatment. Using the new gene signature, survival analysis was conducted and a metastasis risk score was developed that provides a practical tool for assessing the risks of metastasis. In the second part, structure-based virtual screening was adopted to investigate which of the already FDA approved drugs can be potentially repositioned to be used against tuberculosis. Because of their known profiles of ADMET, repositioning known drugs for novel indications can shorten the length of time of drug discovery and increase the rate of success. Using virtual screening with molecular docking, a short list of compounds targeting essential TB proteins was identified. More investigations would be needed to further study the potential of the docking hits as repositioning candidates. In the third part, the relationships between moonlighting proteins and diseases were reviewed, and characteristics that correlate with proteins performing moonlighting functions were illustrated. Moonlighting proteins are proteins that have more than one biochemical or biophysical function performed by the same peptide chain. The switching of functions can be activated by a variety of elements such as expression in different cellular localizations. By having moonlighting functions, proteins can coordinate multiple cellular processes in cellular metabolism, which is essential for health. In conclusion, my analysis of gene expression and investigations of protein structure and function explored in three specific areas, which contributes to a better comprehension of the molecular mechanisms of health and disease.