Background/Objectives: Neutrophil cells lysis forms the extracellular traps (NETs) to counter the foreign body during insults to the body. Peptidyl arginine deiminase (PAD) participates in this process and is then released into the extracellular fluid with the lysed cell components. In some diseases, patients with abnormal function of PADs, especially PAD 4, tend to form autoantibodies against the abnormal citrullinated proteins that are the result of PAD activity on arginine side chains. Those antibodies, which are highly distinct in RA are distinctly anti citrullinated protein antibodies (ACPA). This study used an in-silico drug repurposing approach of FDA approved medications to identify potential alternative medications that can inhibit this process and address solutions to the current limitations of existing therapies. Methods: We utilized Maestro Schrödinger as a Computational tool for preparing and docking simulations on the PAD 4 enzyme crystal structure that is retrieved from RCSB Protein Data Bank (PDB ID: 4X8G) while the docked FDA-approved medications are obtained from Zinc 15 database. The protein was bound to GSK 199 -investigational compound- as positive control for the docked molecules. Preparation of the protein was done by Schrödinger Protein Preparation Wizard tool. Binding Pocket Determination was done by Glide software and Validation of Molecular Docking carried out through redocking of GSK 199 and superimposition. After that, standard and induced fit docking were done. In molecular dynamics Desmond System Builder was utilized where the receptor-ligand complex was immersed in the TIP3P solvent model with a buffer containing 0.15M NaCl. ADMET properties prediction of hits were run by pkCSM website. Results/Conclusions: Among the four obtained hits Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, which showed the highest XP scores providing favorable binding interactions. The induced-fit docking (IFD) results displayed strong binding affinities of Ioversol, Pemetrexed, Leucovorin, Chlordiazepoxide in the order IFD values -11.617, -10.599, -10.521, -9.988, respectively. This research investigates Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol as potential repurposing agents in the treatment of rheumatoid arthritis (RA) as identified as PAD4 inhibitors. Keywords: PAD4; PAD IV; Rheumatoid arthritis; PAD4 activity; PAD4 inhibitor; Citrullination; Peptidyl arginine deiminase.

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