Computational modeling approaches have been instrumental to biological and biochemical researchfor over 50 years, providing insight that can impact advances in human, animal, and environmental health. The use of in silico methods in drug discovery can reduce financial cost and time required for the development of new drugs by providing molecular-level insight and information about structure-activity relationships. Computational chemistry approaches can provide compound identification, optimization and screening towards the development of more potent and novel molecules. Computational biophysical methods are not only useful in drug discovery, but they are also useful in environmental science as well, in areas such as determining the toxicity of pollutants. The validation of computational protocols is an important step in computational modeling. SAMPL blind challenges provide host-guest systems with known binding affinities and physical properties to benchmark developed methods and protocols against experiment. A benchmark for the protocols used throughout the dissertation has been provided. Per- and polyfluoroalkyl substances (PFAS) are man-made molecules that have very interesting chemical features. These compounds are both water and oil-resistant therefore, they have been utilized in many industrial processes and household products, including fast food packaging, firefighting foams, dental floss, water-resistant garments, batteries, and non-stick cookware. However, research conducted in recent years has shown that some PFAS can cause significant health problems thyroid problems, cholesterol and lipid issues, and cancer in living organisms upon consistent exposure and bioaccumulation. Several of the chapters in this dissertation highlight investigations of three different protein targets of PFAS: • human Peroxisome proliferator receptor gamma - retinoid x receptor alpha /DNA (PPAR?- RXR?/DNA) is an important protein for regulation of glucose metabolism and fat cell differentiation, • human thyroglobulin protein (hTG) which is responsible for producing the thyroid hormones, • rainbow trout estrogen receptor ? and ? (ER?, ER?) controlling the reproduction. The goal of each of the studies was to gain a molecular-level understanding of the impact of selected common and alternative PFAS on the proteins. In considering specific disease, tuberculosis (TB) is a persistent disease largely observed in rural parts of the world. While there are available treatment regimens for both drug-susceptible as well as drug-resistant TB, these treatment protocols require use of many different drugs and take from six months to up to two years. Therefore, there is a need for the development of better treatment strategies. A chapter in this dissertation highlights how computational chemistry approaches have been used in studies to develop compounds targeting the treatment of Tuberculosis via two different protein targets, mycobacterium membrane protein large 3 (mmpL3) and DosS in collaboration with medicinal chemists. Homology modeling, binding energy estimations, as well as conformational dynamics of these proteins were investigated.
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