In silico targeting PAD4 for the treatment of rheumatoid arthritis
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Rheumatoid arthritis (RA) is an autoimmune disorder that causes chronic inflammation with periodic bursts of activity in multiple synovial joints which lead to irreversible damage of cartilage and bone. Although several drugs that reduce inflammation are used for the treatment of RA, they are often associated with side effects. Therefore, the development or identification of a drug with no side effects or reduced side effects is desirable. Protein arginine deiminases (PADs), a set of key enzymes to trigger autoimmune response necessary for the development of RA, can be targeted for the treatment of RA. In the present study, we had developed a pharmacophore model for PAD type 4 (PAD4) protein comprising single aromatic and three hydrogen acceptor groups. Pharmacophore-based virtual screening upon ZINC database mapped several hits which were subsequently reduced by molecular docking with PAD4 protein structure. The best-scoring two ligands (Zinc_00525911 and Zinc_01225171) selected based on docking energy, pharmacophore fitness, and topology among the hits were further validated using molecular dynamics simulation for 10 ns. These two ZINC hits established interactions with key amino acid residues of PAD4 including H-bonds with Arg 372, Arg 374, Asp 350, and His 471 residues. These prioritized hits can be further tested in the in vitro and in vivo models of RA.
KeywordsRheumatoid arthritis Protein arginine deiminases Structure-based drug design Molecular modeling Pharmacophore screening
This study is financially supported by the Department of Science and Technology, New Delhi as Innovation in Science Pursuit for Inspired Research (INSPIRE) Fellowship.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study does not contain any studies with human participants or animals performed by any of the authors.
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