Life Sciences Commons^™

Biochemical Evaluation Of Drug Inhibition Of Abc Transporters, Maisa Correa De Oliveira

Biological Sciences Theses and Dissertations

Multidrug resistant (MDR) cancers often become resistant to pharmacologically and structurally diverse drugs by overexpressing members of the family of ATP Binding Cassette (ABC) transporters. These membrane pumps protect normal cells by actively exporting a large range of toxins out of the cells. Classic MDR is often correlated with the overexpression of three well-studied mammalian ABC transporters: P-glycoprotein (P-gp), Breast Cancer Resistant Protein (BCRP), and Multidrug Resistant Protein 1 (MRP1).

P-gp is the most studied ABC transporter, and the search for P-gp inhibitors as co-therapeutics to combat MDR has had little success after decades of studies. We previously used high-throughput …

Application Of Artificial Intelligence And Machine Learning In Chemistry, Niraj Verma

Chemistry Theses and Dissertations

In the last four years, I have been exposed to various topics in scientific research under the supervision of Dr. Kraka in the CATCO group. Numerous involved chemistry projects were undertaken to gain an understanding of the basic laws of nature involving vibrational spectroscopy, molecular acidity, and catalysts based on transition metals for halogen chemistry. The insights from computational chemistry were then applied to model and predict various complicated problems in chemistry via artificial intelligence. With the help of classical artificial intelligence, the non-covalent interactions governing the properties of proteins and water properties were analyzed. Significant improvements were made in …

Dynamic Mechanisms Of Multidrug Resistance In Human Cancers And Gram Negative Pathogens, Lauren Ammerman

Biological Sciences Theses and Dissertations

This dissertation focuses upon dynamic agents of multidrug resistance (MDR). We used a combination of in silico and in vitro techniques to investigate two membrane transporters that confer MDR – P-glycoprotein, which confers MDR in human cancers, and MtrD, which confers MDR in Neisseria gonorrhoeae. Inhibitors targeting both proteins have tremendous potential for use as co-therapeutics in the treatment of multidrug resistant cancers, or of multidrug resistant infections. However, previously identified inhibitors of P-gp have failed clinical trials due to off-target effects and associated toxicities. Furthermore, the molecular mechanism of antibiotic transport by MtrD is poorly understood, and this dearth …

Mechanistic Studies Of Drug-Like Inhibitors Of P-Glycoprotein Using Atpase Assays, Electron Spin Resonance Spectroscopy And Cancer Cell Models, Gang Chen

Biological Sciences Theses and Dissertations

Multidrug resistance (MDR) in cancer and other diseases is frequently associated with transmembrane efflux proteins, one of which is P-glycoprotein (P-gp). Over-expression of P-gp in cancer cells increases the efflux of therapeutic drugs rendering them ineffective. In order to re-sensitize multidrug resistant cancers to chemotherapy, we have found potential inhibitors of P-gp by in silico screening methods, and several of these inhibitors were shown to successfully overcome MDR in the drug resistant DU145TXR prostate cancer cell line. The best of the identified hit compounds were further investigated with regard to the mechanism of inhibition using ATPase activity assays and electron …