BACKGROUND: Porphyromonas gingivalis, a major pathogen in periodontitis, produces KGP (Lys-gingipain), a cysteine protease that enhances bacterial virulence by promoting tissue invasion and immune evasion. Recent studies highlight microRNAs' role in viral latency, potentially affecting lytic replication through host mechanisms. Herpes virus (HSV) establishes latency via interactions between microRNA-6 (miRH-6) and the ICP4 transcription factor in neural ganglia. This suggests a potential link between periodontitis and HSV-induced latency. This study aims to identify and validate the insilico inhibitory interaction of P. gingivalis KGP with ICP4 transcripts and correlate the presence of viral latency-associated transcript micro-RNA-6 with periodontitis. METHODS: Computational docking analysis was performed to investigate the potential interaction between ICP4 and KGP gingipain. The binding energy and RMSD ligand values were calculated to determine the interaction's strength. Ten patients with recurrent clinical attachment loss despite conventional therapy were included in the clinical study. Subgingival tissue samples were collected post-phase I therapy, and HSV microRNA-6 presence was detected via polymerase chain reaction and confirmed through gel electrophoresis. RESULTS: Computational docking identified the ICP4-KGP gingipain complex with the lowest binding energy (-288.29 kJ mol^1) and an RMSD ligand of 1.5 Angstroms, indicating strong interaction potential. Gel electrophoresis confirmed miRH-6 presence in all samples. CONCLUSION: The identification of miRNA-6 in periodontitis patients and the strong interaction potential between P. gingivalis KGP gingipain and ICP4 transcripts indicate a possible link between bacterial virulence factors and viral latency dynamics in periodontal tissues. These results highlight the complex interplay between oral pathogens, viral microRNAs, and host immune responses in periodontitis.