TY - JOUR
T1 - A Multifaceted Computational Approach to Identify PAD4 Inhibitors for the Treatment of Rheumatoid Arthritis (RA)
AU - Alturki, Mansour S.
AU - Gomaa, Mohamed S.
AU - Tawfeeq, Nada
AU - Al Khzem, Abdulaziz H.
AU - Shaik, Mohsina B.
AU - Alshaikh Jafar, Murtadha
AU - Alsamen, Mohammad
AU - Al Nahab, Hasan
AU - Al-Eid, Mohammad
AU - Almutawah, Alhassan
AU - Rants’o, Thankhoe A.
AU - Ayil, Khaled A.G.
AU - Almaghrabi, Mohammed
N1 - Publisher Copyright:
© 2025 by the authors.
PY - 2025/3
Y1 - 2025/3
N2 - 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 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/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 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.
AB - 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 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/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 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.
KW - PAD IV
KW - PAD4
KW - PAD4 activity
KW - PAD4 inhibitor
KW - citrullination
KW - peptidyl arginine deiminase
KW - rheumatoid arthritis
UR - https://www.scopus.com/pages/publications/105001305423
U2 - 10.3390/metabo15030156
DO - 10.3390/metabo15030156
M3 - Article
AN - SCOPUS:105001305423
SN - 2218-1989
VL - 15
JO - Metabolites
JF - Metabolites
IS - 3
M1 - 156
ER -