Identification of Novel, Selective Plk1 Inhibitors through Molecular Modeling and Fluorescence Polarization Experiments The long-term goal of the proposed study is to identify novel nonpeptide-based selective inhibitors for polo-box domain (PBD) of polo-like kinase 1 (PLK1) that can be used for targeted cancer therapies. Given its major role in mitotic events, PLK1 is a marker for cellular proliferation with a prognostic potential in some types of cancers. A high level of PLK1 expression is associated with a poor prognosis. Studies have shown that the loss of PLK1 expression can induce apoptosis and inhibit growth in many cancer cells while showing an insignificant effect on normal cells in mouse models. On the other hand, PLK2 and PLK3 have been identified as tumor suppressors. Therefore, selective and specific inhibition of PLK1 is a promising therapeutic strategy for a range of cancer types. In our study, the rationale for targeting the PBD as opposed to the kinase catalytic domain (KCD) is that the KCD is conserved among kinases and therefore poses selectivity and toxicity problems. PLK1 inhibitors will be identified in several steps. (1) Small molecules with known binding profiles to PLK1-3 will be studied through molecular dynamics (MD) simulations to gain atomistic insights for the key interactions needed for strong binding profile for PLK1 but not for PLK2-3. (2) COCONUT natural products database and Atomwise company small molecule database will be screened to identify potential inhibitors. The top hit candidates will be studies through MD and ADMETS (absorption, distribution, metabolism, excretion, toxicity and stability) simulations to reduce the number of candidates and finally the top molecules will be studies through steered MD and fluorescence polarization experiments. The proposed study is innovative in many aspects but particularly its unique design for allowing meaningful participation of Deaf and Hard of Hearing undergraduate and high school students. Major outcome of the study is that it is expected to provide a starting point for a drug design pipeline for the PBD of PLK1 and further guide the in vivo experiments and/or clinical considerations.