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In silico targeting PAD4 for the treatment of rheumatoid arthritis

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Abstract

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.

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Funding

This study is financially supported by the Department of Science and Technology, New Delhi as Innovation in Science Pursuit for Inspired Research (INSPIRE) Fellowship.

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Authors and Affiliations

  1. Department of Botany, Bioinformatics, and Climate Change Impacts Management, Gujarat University, Ahmedabad, Gujarat, 380 009, India

    Mehul N. Soni, Sivakumar Prasanth Kumar & Himanshu A. Pandya

  2. Department of Zoology, Bio-Medical Technology and Human Genetics, Gujarat University, Ahmedabad, Gujarat, 380 009, India

    Kaid Johar SR

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  1. Mehul N. Soni
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  2. Sivakumar Prasanth Kumar
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  3. Kaid Johar SR
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  4. Himanshu A. Pandya
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Correspondence to Himanshu A. Pandya.

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Soni, M.N., Kumar, S.P., Johar SR, K. et al. In silico targeting PAD4 for the treatment of rheumatoid arthritis. Struct Chem 30, 1323–1334 (2019). https://doi.org/10.1007/s11224-018-1263-5

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