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Fluorescence-based Monitoring of PAD4 Activity via a Pro-fluorescence Substrate Analog
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A Multifaceted Computational Approach to Identify PAD4 Inhibitors for the Treatment of Rheumatoid Arthritis (RA)
Mansour S Alturki1, Mohamed S Gomaa1, Nada Tawfeeq1
1Department of Pharmaceutical Chemistry, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia.
Metabolites
|March 26, 2025
Summary
This study identified four FDA-approved drugs—Ioversol, Pemetrexed, Leucovorin, and Chlordiazepoxide—as potential inhibitors of PAD4. These drugs show promise for repurposing in rheumatoid arthritis (RA) treatment by targeting neutrophil extracellular traps (NETs).
Area of Science:
- Computational chemistry and drug discovery
- Molecular modeling and simulation
- Pharmacology and medicinal chemistry
Background:
- Neutrophil extracellular traps (NETs) are formed during cellular lysis to combat foreign bodies.
- Peptidyl arginine deiminase 4 (PAD4) plays a role in NET formation and is implicated in autoimmune diseases like rheumatoid arthritis (RA).
- PAD4 activity leads to citrullinated proteins, which can trigger autoantibody production (ACPA) in RA patients.
Purpose of the Study:
- To identify FDA-approved medications for drug repurposing as potential inhibitors of PAD4.
- To explore novel therapeutic strategies for rheumatoid arthritis (RA) by targeting PAD4 activity.
- To address limitations of current RA therapies through computational drug discovery.
Main Methods:
- Utilized Maestro Schrödinger for computational docking simulations of FDA-approved drugs against the PAD4 enzyme.
- Retrieved PAD4 crystal structure from the Protein Data Bank (PDB ID: 4X8G) and used the Zinc 15 database for drug candidates.
- Performed molecular docking, including standard and induced-fit docking, with validation using a known inhibitor (GSK 199).
Main Results:
- Identified four potential drug candidates: Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol, based on high docking scores (XP scores).
- Induced-fit docking (IFD) revealed strong binding affinities for these compounds, with Ioversol (-11.617), Pemetrexed (-10.599), Leucovorin (-10.521), and Chlordiazepoxide (-9.988).
- These compounds demonstrated favorable binding interactions with the PAD4 enzyme.
Conclusions:
- Pemetrexed, Leucovorin, Chlordiazepoxide, and Ioversol are identified as potential PAD4 inhibitors.
- These identified drugs are proposed as candidates for repurposing in the treatment of rheumatoid arthritis (RA).
- The study highlights the potential of in-silico drug repurposing for developing new RA therapies targeting PAD4.
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