ArticleMetabolites2025
A Multifaceted Computational Approach to Identify PAD4 Inhibitors for the Treatment of Rheumatoid Arthritis (RA).
Article in Metabolites, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- A multi-stage computational pipeline for repurposing FDA-approved drugs: application to EGFR C797S-mutant NSCLC.Frontiers in chemistry · 2026Article
- Peptidylarginine deiminase 4-mediated citrullination in human disease: molecular mechanisms and therapeutic targeting.Frontiers in pharmacology · 2026Review
- Peptidylarginine Deiminases: An Overview of Recent Advances in Citrullination Research.International journal of molecular sciences · 2025Review
- Structure-Based Discovery of Orthosteric Non-Peptide GLP-1R Agonists via Integrated Virtual Screening and Molecular Dynamics.International journal of molecular sciences · 2025Article
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Authors and funding
13 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND/
objectivesNeutrophil 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.
methodsWe 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 the Zinc 15 database. The protein was bound to GSK 199-an investigational compound-as a positive control for the docked molecules. Preparation of the protein was performed by Schrödinger Protein Preparation Wizard tool. Binding pocket determination was performed by Glide software (Schrödinger Release 2021-3:Schrödinger, LLC., New York, NY, USA, 2021). and validation of molecular docking was carried out through the redocking of GSK 199 and superimposition. After that, standard and induced fit docking were performed. RESULTS/
conclusionsAmong 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 the 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 they are identified as PAD4 inhibitors.
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