HIV, the causative virus of AIDS, has posed a severe threat to global health for an extensive period. Recent statistics show the magnitude of this challenge, with approximately 2.4 million people in India living with HIV, along with 41.97 thousand deaths which were reported in 2021. In the face of this on-going crisis, patients have relied heavily on anti-retroviral therapies, among which Rilpivirine stands out as a key treatment option, particularly for individuals exhibiting low viral loads. However, the efficacy of Rilpivirine diminishes significantly in patients against high viral loads of HIV-1C, leading to the emergence of drug-resistant strains. Consequently, there exists an urgent need to identify and develop more potent therapeutic agents to combat HIV infection. To address this, we performed an in-silicon investigation, utilizing virtual screening tools to explore potential alternative drugs to Rilpivirine for HIV treatment. Our methodology involved mining data from reputable sources such as the PubChemand Zinc databases to identify compounds with potential antiretroviral activity. We subjected these compounds to screening using the SwissADME tool, evaluating their pharmacokinetic characteristics and adherence to Lipinski's rule of five. Compounds demonstrating favourable properties, as indicated by zero violations in OSIRIS Property Explorer, were then prioritized for further analysis. The structural frameworks of Rilpivirine protein-ligand complexes, both native (7Z2D) and mutant (7Z2E) variants, were procured from the Protein Data Bank (PDB). Further, ligand molecules' structural configurations were sourced from databases such as PubChem and Corinasoftware. Employing molecular docking simulations facilitated by HDOCK docking software, the binding affinities of these ligands against the receptor protein-ligand complexes were studied, from which, Schumannificine emerged as the most promising candidate, exhibiting the most stable binding interactions.In summation, out of 65 phytochemicals, our comprehensive investigation underscores the potential of Schumannificine (CID: 184890), an alkaloid compound derived from the Schumanniophytonmagnificum plant as a novel and viable therapeutic option for HIV patients. © The Authors.