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University of Macau / Institute of Chinese Medical Sciences

Membrane transporters are essential for the transfer of hydrophobic molecules across the plasma membrane of cells; therefore active and facilitated transport processes can determine the absorption, distribution, metabolism and excretion profile of drugs.

Thesis (Ph. D.)--University of Rhode Island, 2003. / Typescript. Includes bibliographical references (leaves 202-211).

Thesis (M.S.)--Rowan University, 2005. / Typescript. Includes bibliographical references.

Experimental methodological developments in measuring protein-ligand interactions for small molecule (<900 Da) drug discovery have led to an influx of data. In some instances this data overload has been overwhelming and can complicate rather than inform decision-making during drug discovery. The focus of this thesis is thus to develop novel methods to contextualise and extract useful information that helps medicinal and computational chemists make sense of available data and improve the productivity of drug discovery. Specifically I have developed computational tools to structure and analyse protein-ligand interaction data. I generated 48 novel ligand-bound protein structures for the bromodomain of BAZ2B and the JmjC domain of KDM4 using experimental fragment soaking. This quantity of structures required time consuming and subjective analysis. A 3D interactive visualisation tool, WONKA, was therefore developed. WONKA displays interesting and unusual features (e.g. residue motions) within ensembles of protein-ligand structures and allows for sharing of observations between scientists. WONKA does not consider protein-ligand activity data, so I developed OOMMPPAA. OOMMPPAA is an interactive 3D visualisation tool that incorporates protein-ligand activity data with protein-ligand structural data using 3D matched molecular pairs. OOMMPPAA highlights nuanced structure activity relationships (SAR) and summarises available protein-ligand activity data in the protein context. WONKA and OOMMPPAA form a data model and platform to analyse structural and activity data. The extensibility and utility of this data model are demonstrated by the development of two further tools. The first, GLOOP, suggests ligand modifications from large datasets, and provides quantification of the importance of putatively important moieties. The second, LLOOMMPPAA, designs synthetically tractable molecules that explore a diverse range of protein-ligand interactions. LLOOMMPPAA has been shown experimentally to provide useful SAR. The tools described in this thesis provide novel analyses of and a framework for investigating protein-ligand interaction data.

Background: Exosomes are extracellular vesicles (EVs) that produced in the endosomal compartment of most eukaryotic cells, and have observed increasing attentions over the past decades. They play important roles in cell- to-cell communications, they can carry varieties of substances, like proteins, nucleic acids and lipids, to the target cells they encounter. These cargos could influence the function of recipient cells. This novel mode of intercellular communication is found to be of critical importance to many cellular activities. However, exosomes are involved in various diseases processes. Tumor- derived exosomes could promote cancer progression, and our preliminary study indicated that exosome released from osteoclasts could inhibit bone formation. We also found that osteoarthritis (OA) progression in OA mice could be attenuated by inhibiting exosomes released by osteoclasts. Therefore, inhibition of exosome release has potential value in the treatment of diseases. The exosome release is under control by RAB27A, which is a protein involved in protein transport and signal transduction. It is reported that a compound named Nexinhib20 could selectively inhibit RAB27A, but this compound is highly toxic to RAW264.7 cells, which IC 50 is 1.5 µM. Therefore, for safety concerns, it has to be chemically modified to reduce toxicity. Aim: (1) To design and synthesize a series compounds based on the structure of Nexinhib20. (2) To evaluate the toxicity and exosome inhibiting activity of the synthesized compounds and discuss the structure-activity relationships (SAR) of them. Materials and Methods: Nexinhib20 derivatives were synthesized by aldol reaction. The cytotoxicity of these compounds was evaluated by MTT assay. The exosome inhibiting activity of these compounds was evaluated through exosome isolation and quantitation. Result: A series of compounds were synthesized and their structures were confirmed by LC-MS and NMR. The structure-activity relationships of these compounds were discussed, and the results showed that compounds A3, A23 and B2 exhibited lower toxicity compared to Nexinhib20 and strong exosome inhibiting ability. Conclusion: The results of this project indicate that A3, A23 and B2 exhibited low toxicity and good exosome inhibiting activity. Based on this, further chemical modification could be applied to develop new exosome inhibitors with better efficacy

Thesis (Ph. D.)--Ohio State University, 2008. / Title from first page of PDF file. Includes bibliographical references (p. 210-232).

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