Publication: DYSREGULATION OF CITRULLINATION BY ORAL BACTERIA AND ITS EFFECT ON NEURODEGENERATIVE DISORDERS: A SYSTEMATIC REVIEW AND IN SILICO STUDY
Date
2026
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Publisher
IMU University
Abstract
Emerging evidence of meta-analyses suggested that periodontal disease (PD) mediated by oral bacteria may increase the risk of developing neurodegenerative disorders. However, the findings were inconsistent and inconclusive. An umbrella review makes it feasible to summarise the current evidence from the published meta-analyses on this topic and enable the ranking of evidence. In addition, among periodontal pathogens, Porphyromonas gingivalis produces a calcium-independent peptidylarginine deiminase enzyme (PPAD) that induces hypercitrullination, a process that has been proposed to contribute to the onset of neurodegenerative disorders. Nonetheless, PPAD inhibitors have been scarcely reported in the literature, highlighting a significant gap in the current body of research. Therefore, this study aimed to (i) conduct an umbrella review to summarise the associations between oral bacterial diseases and neurodegenerative disorders and assess the credibility of evidence supporting such associations and (ii) evaluate the binding interactions and identify potential inhibitors of PPAD through molecular docking simulations, using the 15 compounds previously identified via 2D ligand-based similarity screening. An umbrella review of 6 eligible meta-analyses including 17 associations was conducted using predefined eligibility criteria and the credibility of evidence was graded according to AMSTAR-2 methodological quality assessment. In parallel, molecular docking simulations were performed to examine binding affinity and key residue interactions of 15 compounds within the PPAD binding site. Nine of 17 associations (52.9 %) showed statistical significance at P ≤ 0.05 based on random-effects models between PD and neurodegenerative disorders. Twelve out of the 17 associations (70.6%) had considerable heterogeneity (I2 > 50%), suggesting that the pooled estimates should be interpreted carefully. Only one association from 17 associations showed a small-study effect. Docking analyses revealed that several compounds exhibited favourable binding affinity within the PPAD binding site interacting with essential residues, particularly (4S)-5-[[(2S)-1-[[(2S)-1-Amino-3-[4-[difluoro(phosphono)methyl]phenyl]-1-oxopropan-2-yl]amino]-3-[4-[difluoro(phosphono)methyl]phenyl]-1-oxopropan-2-yl]amino]-4-benzamido-5-oxopentanoic acid exhibiting binding score of -9.737 kcal/mol. Notably, N-acetyl-L-arginine was estimated to interact directly with His236 of the catalytic triad, suggesting potential inhibition. Collectively, the umbrella review and molecular docking simulations support a biological plausible, though not definitive, link between PD and neurodegenerative disorders. Further longitudinal studies and experimental enzymatic and cellular evaluations are necessary to enhance PPAD-target inhibitor development toward clinical application.
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Keywords
Periodontal Diseases, Neurodegenerative Diseases, Porphyromonas gingivalis, Citrullination, Molecular Docking Simulation, Systematic Reviews as Topic