Paper Title
Anti-Proliferative Effect of Potential LSD1/Corest Inhibitors based on Molecular Dynamics Model for Treatment of Sh-Sy5y Neuroblastoma Cancer Cell Line

Lysine-specific demethylase is a demethylase enzyme that can remove methyl groups from histones H3K4me1/2 and H3K9me1/2. It is expressed in many cancers, where it impedes differentiation and contributes to cancer cell proliferation, cell metastasis and invasiveness, and is associated with inferior prognosis. LSD1 is associated with its corepressor protein CoREST, and utilizes tetrahydrofolate as a cofactor to accept CH2 from the demethylation process.The fact that the cofactor is best bound to the active site inspired us to explore its interactions to LSD1/CoREST enzyme complex utilizing molecular dynamics simulation, which aids designing novel and potent inhibitors. The model derived from the molecular dynamics simulation study and the key contacts to the active site were used in the subsequent structure based drug design and in-silico screening, which revealed a number of potential inhibitors toward LSD1/CoREST complex. In silico mining on National Cancer Institute (NCI) database identified 55 promising and structurally diverse inhibitors.The anti-proliferative activities of the identifiedcompounds were tested against neuroblastomaSH-SY5Y cancer cell linewhich known to highly express LSD1/CoREST complex. Applying the abovementioned molecular modeling procedure yielded four compounds of LSD1/CoREST inhibiters with IC50<2µM, when tested against SH-SY5Y cells, IC50 = (1.52, 0.195, 1.06 and 1.08µM). To test their toxicity, the compounds were tested against normal fibroblast cells. These compounds are excellent candidates for further optimization. Keywords- In-silico Screening, Lysine-specific Demethylase 1 (LSD1), Neuroblastoma, Molecular Dynamics Simulation.