Indiana University-Purdue University Indianapolis (IUPUI) / Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects over 10 million people. Treatments for PD are limited to symptom mitigation with no means of stopping or slowing disease progression. Mutations within the protein leucine- rich repeat kinase 2 (LRRK2) are the most common cause of familial PD and are indistinguishable from the more common sporadic cases. Identifying molecules capable of modulating LRRK2 GTPase activity may serve as the foundation for future development of novel PD therapeutics. We recently discovered that the G-domain (ROC) of LRRK2 is capable of transitioning between monomer and dimer form in solution upon GTP/GDP binding. R1441C/G/H pathogenic mutations were demonstrated to alter this dynamic shifting toward a monomeric ROC conformation while decreasing GTPase activity. Using our ROC dimeric crystal structure, we strategically introduced disulfide bonds to generate locked monomer and locked dimer states. Monomeric ROC was shown to increase GTPase activity while the dimeric form decreased activity. Solvent mapping performed using the dimeric ROC crystal structure and a homology model of the ROC monomer revealed a binding hotspot at the ROC dimeric interface and adjacent to the R1441 residue in the monomeric model. In this study our goal was to identify more compounds capable of influencing GTPase activity. We performed high throughput screening of ROC against two compound libraries (LOPAC1280 and ChemBridge 50K) in a GTP binding assay. Twenty-three hits were identified and four compounds were further investigated in dose-response experiments. 3,4-Methylenedioxy-beta nitrostyrene (MNS) was demonstrated to decrease GTP binding and inhibit GTPase activity (IC50=23.92μM) while the compound N-phenylanthranilic acid increased GTP binding (EC50=4.969μM) and decreased GTPase activity. Identification of these compounds is the first step in the development of a novel PD therapeutic targeting the G-domain of LRRK2.