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CHARACTERIZING FINE-TUNED 4-AMINOQUINONLINE DERIVATIVES AS NOVEL ANTIVIRAL LIGANS FOR COVID-19**

Abstract

The rapid emergence of SARS-CoV-2 variants continues to compromise the effectiveness of current antivirals and vaccines by altering viral protein structure and drug-binding sites. In this study, forty-two quinoline-4-amine derivatives were evaluated as potential COVID-19 therapeutics through molecular docking against eight viral receptors, including the spike glycoprotein (PDB ID: 6VXX). Binding affinities ranged from –5.00 to –9.00 kcal/mol, driven by a combination of hydrogen bonding and aromatic hydrophobic interactions. Aminoquinoline-240 and its four fine-tuned derivatives surpassed the binding affinity of Remdesivir by up to 0.15 kcal/mol for the wild-type spike protein and by 0.892 kcal/mol for the Omicron variant, with all variants showing consistently strong ligand recognition. To deepen mechanistic understanding, Fragment-Based Symmetry-Adapted Perturbation Theory (FSAPT) calculations using Promethium will be employed to map key electrostatic and dispersion-driven determinants of active-site recognition. Additionally, molecular dynamics simulations will be used to generate free-energy binding profiles for the top candidates, enabling refinement of ligand design and prioritization. Together, these results highlight 4-aminoquinolines as promising scaffolds for next-generation antiviral development against evolving SARS-CoV-2 variants.

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