Network Pharmacology and Systems-Level Deconstruction of Multi-Target Phytochemicals from Ocimum sanctum against the HIV-1/Host Interactome: A Dual Virology-Metabolic Interface Study

Abstract

Background: Human Immunodeficiency Virus Type 1 (HIV-1) systematically alters host cellular networks, triggering chronic hyper-inflammation while aggressively disrupting host lipid and glucose pathways (Arya et al., 2024; Kondapalli et al., 2022). While conventional antiretroviral therapy (cART) effectively suppresses viral replication, it often fails to resolve—and can at times worsen—these metabolic abnormalities (Bhattarai et al., 2024). Objective: This study implements an integrated network pharmacology, systems biology, and computational docking pipeline to deconstruct the multi-target mechanism of active phytometabolites from Ocimum sanctum (Tulsi) at the host-HIV-1 virology-metabolic interface. Methodology: Bioactive constituents of O. sanctum were screened using strict drug-likeness rules (Oral Bioavailability ≥30%, Drug-Likeness ≥0.18) (Chaudhary et al., 2020). Target profiles for representative volatile phenylpropanoids (Eugenol) and pentacyclic triterpenoids (Ursolic Acid) were mapped via SwissTargetPrediction and validated through molecular docking using AutoVina scores against key target pockets (COX-2/5F19, PTPN1/1XBO, and PPARG/3PRG). Downstream network deconstruction was executed via the Metascape bioinformatics suite (Zhou et al., 2019). Results: Reverse screening and molecular docking isolated two distinct structural networks showing clear therapeutic alignment. Phenylpropanoids (Eugenol) clustered significantly under the Biosynthesis of DPA-derived Specialized Pro-resolving Mediators (SPMs), forming a tight core interactome sub-network with PTGS2 (COX-2), yielding a maximum Vina docking affinity of −6.6 kcal/mol at pocket C4. Conversely, pentacyclic triterpenoids (Ursolic Acid) targeted host metabolic architecture with high confidence. Ursolic Acid displayed a powerful docking affinity of −9.4 kcal/mol against the nuclear receptor PPARG (3PRG, pocket C1) and −7.1 kcal/mol against PTPN1 (1XBO, pocket C2), driving the negative regulation of lipid storage and fatty acid metabolic processes. Both pathways logically converged on upstream regulators STAT6, JUN, and the RELA/NFKB1 transcription complex. Conclusion: O. sanctum displays a highly coordinated dual-interface mechanism. The volatile fraction targets the virology interface by boosting anti-inflammatory pro-resolving lipid pathways, while the triterpenoid fraction acts directly at the metabolic interface to protect host cellular architecture from virus-induced lipid hijacking. This offers a robust computational blueprint for developing adjunctive, dual-action therapies against chronic retroviral complications.