Repurposing of FDA-Approved Drugs as Inhibitors of Porphyromonas Gingivalis Peptidylarginine Deiminase (PPAD), a Causal Agent of Rheumatoid Arthritis

Chow, Yoke Chan (2021) Repurposing of FDA-Approved Drugs as Inhibitors of Porphyromonas Gingivalis Peptidylarginine Deiminase (PPAD), a Causal Agent of Rheumatoid Arthritis. Masters thesis, Tunku Abdul Rahman University of Management and Technology.

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disease in which synovial tissue is destroyed, resulting in severe joint damage and inflammation. Common treatments of RA symptoms have been the preferred method of keeping RA at bay, but this treatment option does not adequately address or eliminate the root cause of RA. Recent findings have been able to correlate P. gingivalis peptidylarginine deiminase (PPAD)-citrullinated peptides to the synovium damage observed in cases of RA, making PPAD a potential therapeutic target. This research aims to repurpose FDA drugs to identify PPAD inhibitors for the treatment of RA. FDA compounds will be curated from ZINC12 and prepared for molecular docking using GLIDE. Identified hit compounds can then be evaluated in vitro through citrullination colorimetric assay. Computational screening of 1495 FDA compounds available through ZINC12 led to the identification of 10 hit compounds to be tested in the citrullination colorimetric assay. The interactions observed between the 10 hit compounds and the important residues in the PPAD active site conferred strong binding activity, later confirmed through the citrullination colorimetric assay with the use of recombinantly-produced PPAD. Three compounds that demonstrated strong inhibition against PPAD in vitro were identified to be Flucytosine, Carmustine and Cytarabine. Flucytosine, Carmustine and Cytarabine were found to be moderate PPAD inhibitors with favourable interactions computationally observed between them and the PPAD active site, which can be further validated through in vivo systems that test for RA.