Date of Award

Fall 12-14-2018

Document Type


Degree Name

Master of Science in Chemistry (MSChem)



First Advisor

Dr. Zegar

Second Advisor

Dr. Mcafee

Third Advisor

Dr. Tayo

Fourth Advisor

Dr. Santera


Lysine demethylase 3A (KDM3A) is an enzyme that specifically catalyzes the removal of 2 or three methyl groups from lysine 9 of histone 3 (KH3). It belongs to the family of histone demethylases that contain the Jumonji C (JmjC) domain, which means cruciform in Japanese. KDM3A also belongs to a family of hydroxylases that are alpha-ketoglutarate dependent. The role of KDM3A in the cell is not yet understood, however, and based on its demethylation of studies have showed that its expression is elevated in embryonic stem cells in humans and in mice. In general, patterns of elevated expression of KDM3A gene have been associated with cell differentiation and cell proliferation in several tissues. Studies have also shown that KDM3A was found to be overexpressed in breast cancer cells, and it is believed to be associated with the regulation of estrogen receptors and with breast cancer growth and metastasis. KDM3A is also found to be upregulated in small cell lung cancer cells which are the least common of lung cancer cells but the most aggressive. Other cancer cells that KDM3A has been associated with and is found to undergo enhanced expression are prostate cancer and the nervous system cancer cells. In all of those cancers, KDM3A was found to be linked to the role of promoting cancer stem cell progression and resistance to chemo and radiation therapy. This role is primarily attributed to the role of JimjC domains of KDM3A in demethylating KH3 which is known to result in gene repression of the tumor suppression protein, p53 and in the formation of inactive heterochromatin. The goal of this thesis is to begin a drug discovery process in order to determine potential therapeutic agent(s) that can bind the JmjC domain of KDM3A and ultimately inhibit its catalytic activity of the demethylation of KH3. The first step in this process is to conduct a virtual screening study where a large library of small molecule structures is examined for their interactions with the JmjC domain of KDM3A. To do this the coordinates of the three-dimensional structure of the JmjC domain along with the approximate coordinates that outline possible binding sites to be occupied are inputted in a computer software as the receptor molecule, and its binding search space. A large number of structures of ligands from small molecule databases are then used to find a set of ligands that form the most energetically favorable complex with the protein receptor site. Once a set of protein ligand complexes have been determined, we screened the whole library of complexes for those with the highest binding affinities to the protein receptor. Further analysis was also conducted regarding the types of interactions between the ligand and the receptor and how close their binding sites are to the crucial catalytic region of KDM3A. The objective would be to choose the ligand that binds the tightest to KDM3A and blocks and introduces the most hindered conformation to the catalytic site. A total of six small molecules that fulfilled one or both of the above requirements were chosen. A next step will be to experimentally determine the effect of these six compounds on the catalytic activity of KDM3A and to determine the cytotoxic effect on cancer cells.


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