Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disorder that is still unknown in its cause. It is more common in females than males. There are several therapeutic options available for RA, including DMARDS, biological DMARDS, T and B cells targeted therapy, Interleukin targeted therapy, and RANKL inhibitors. Peptidylarginine-deiminase IV (PAD4) are enzymes that are abundant in neutrophils and are believed to drive citrullination under inflammatory conditions. Citrullination can alter the protein structure, creating a new epitope that is recognized by the immune system. PADs catalytic activity requires high calcium concentrations, and hyperactivation of PAD4, which is overproduced in RA, can cause overproduction of deiminated proteins, leading to immune attack on joint tissues. Halo amidines and GSK199 are compounds that can block PAD4 activity but have metabolic and membrane permeability drawbacks, and there is no FDA-approved drug for PAD4. Therefore, our goal is to repurpose some FDA-approved drugs to target PAD4 using a computational drug repurposing strategy.

A total of 1650 FDA-approved drugs were retrieved from the Zinc 15 database and were then prepared and filtered using Maestro software, resulting in 1590 unique compounds. Molecular docking was performed on the crystal structure of the human PAD4 protein in the antagonist state, which was obtained from the Protein data bank (PDB code: 4X8G). 263 drugs that can bind to PAD4 were identified using High Throughput Virtual Screening (HTVS), and after further Standard-precision (SP) and extra-precision (XP), 5 drugs were obtained (Ioversol, Pemetrexed, Leucoverin, Chlordiazepoxide, Chlorthalidone), which were then subjected to Shape Screening, and Induced Fit Docking to validate the binding.

The findings of this study suggest that these hits could have potential therapeutic benefits for RA treatment. Further research will be conducted to examine the efficacy of these hits on PAD4 through molecular dynamics and in vitro studies.