In-Silico Validation of a Quadruple-Target Inhibition Strategy for Orthohantavirus Using Lead Compound Octavir-1q

📄 TECHNICAL NOTE: IN-SILICO VALIDATION OF A QUADRUPLE-TARGET INHIBITION STRATEGY FOR ORTHOHANTAVIRUS USING LEAD COMPOUND OCTAVIR-1Q Author: Shanmithaa . S Affiliation: Independent Researcher, Tiruppur, Tamil Nadu, India Date: May 2026 Document ID: OCTA-2026-001-TN Keywords: Hantavirus, Molecular Docking, Drug Discovery, Orthohantavirus, Bioinformatics, Integrin αvβ3 1. ABSTRACT The ongoing Hantavirus outbreaks (Andes and Puumala strains) present a significant global health challenge due to high mortality rates and the lack of FDA-approved therapeutics. This study utilises computational molecular docking and pharmacokinetic profiling to validate a novel, broad-spectrum antiviral lead, designated as Octavir-1Q. Unlike traditional monotherapy, Octavir-1Q targets four distinct critical checkpoints in the viral lifecycle: replication, attachment, fusion, and host-cell entry. In-silico results demonstrate exceptionally high binding affinities (ΔG) ranging from -8.2 to -9.9 kcal/mol, coupled with a favourable Toxicity Class 5 profile. 2. INTRODUCTION Orthohantaviruses are zoonotic pathogens causing Hantavirus Pulmonary Syndrome (HPS) and Hemorrhagic Fever with Renal Syndrome (HFRS). Current clinical management is primarily supportive. The challenge in drug design is the high mutational rate of RNA viruses. This research proposes a "multi-key" approach, targeting both viral structural proteins and the host-cell entry receptor to minimise the probability of viral escape through mutation. 3. METHODOLOGY The computational pipeline involved three primary stages: Target Selection: Structural data were retrieved from the RCSB Protein Data Bank (PDB). Targets included the Andes virus nucleocapsid core (5E04), Puumala virus Gn glycoprotein (6Y6P), Hantaan virus Gc glycoprotein (5OPG), and the human host receptor Integrin αvβ3 (1L5G). Molecular Docking: Site-specific docking was performed to identify binding energies within the primary active pockets and the Metal Ion-Dependent Adhesion Site (MIDAS) motif of the host receptor. ADMET Profiling: The lead compound, Octavir-1Q, was evaluated using SwissADME for pharmacokinetic parameters and ProTox-3.0 for toxicity modeling. 4. RESULTS AND DATA ANALYSIS 4.1 BINDING AFFINITIES Molecular docking revealed a consistent high-affinity profile across all four targets. Target Category Protein Target (PDB ID) Affinity (ΔG) Biological Impact Replication Andes Virus Nucleocapsid (5E04) -9.9 kcal/mol Disruption of RNA encapsidation Attachment Puumala Virus Gn (6Y6P) -9.3 kcal/mol Blockade of viral-cell tethering Fusion Hantaan Virus Gc (5OPG) -8.8 kcal/mol Inhibition of membrane fusion Entry Human Integrin αvβ3 (1L5G) -8.2 kcal/mol Competitive inhibition at host gate 4.2 PHARMACOKINETICS AND SAFETY Octavir-1Q demonstrates a strong "druggability" profile: • Lipinski’s Rule of Five: Fully Compliant. • PAINS Alerts: 0 (indicates high specificity and zero interference). • Oral Bioavailability Score: 0.56. • Toxicity: Predicted LD₅₀ of 3500 mg/kg (Toxicity Class 5). 5. DISCUSSION The -9.9 kcal/mol affinity against the nucleocapsid core (5E04) suggests that Octavir-1Q may effectively arrest viral replication by preventing the encapsidation of viral RNA. Furthermore, the -8.2 kcal/mol affinity at the human Integrin receptor indicates a "shielding" effect, potentially preventing the virus from utilizing the αvβ3 pathway for cellular entry. Future Optimization: Current models indicate a Fraction Csp³ of 0.11 and potential Blood-Brain Barrier (BBB) permeability. Future structural iterations will focus on increasing carbon saturation (Csp³) to enhance 3D complexity and reduce potential neurotoxicity flags (currently predicted at 0.56 probability). 6. CONCLUSION The in-silico data support Octavir-1Q as a highly viable scaffold for broad-spectrum anti-hantaviral development. The multi-target strategy provides a robust framework for preventing viral entry and replication simultaneously. Immediate in-vitro testing is recommended to validate these computational findings. 7. REFERENCES Borgnia, et al. (2016). Crystal structure of Andes virus nucleocapsid protein. PDB ID: 5E04. Rissanen, et al. (2017). Structure of Hantaan virus Gn glycoprotein. PDB ID: 5OPG. Serris, et al. (2020). Structure of Puumala virus Gn glycoprotein. PDB ID: 6Y6P. Xiong, et al. (2001). Crystal structure of the extracellular segment of integrin αvβ3. PDB ID: 1L5G.