Integrated DFT, DOS, and molecular docking study of oxazine derivatives as promising scaffolds for Anti-HMPV drug design

Abstract

• DFT and TD-DFT analyses reveal charge-transfer behavior in oxazine derivatives. • DOS calculations indicate semiconducting features modulated by heteroatoms. • Hirshfeld and MEP analyses identify key supramolecular interaction sites. • Docking studies suggest oxazine scaffolds as promising in silico anti-HMPV leads. Oxazine derivatives 1–3 was investigated through density functional theory (DFT at B3LYP/6-311G basis set, time-dependent DFT (TD-DFT) in this study and the molecular Hirshfeld surface analysis (HSA), molecular electrostatic potential (MEP) mapping, and molecular docking analyses were utilized to evaluate the electronic, structural and computationally predicted binding affinity. DFT and TD-DFT calculations revealed that the derivatives behave as semiconductors with tunable HOMO–LUMO gaps energies with values ranging from 3.09 to 5.36eV, dominated by intramolecular charge-transfer interactions that modulate their absorption properties. Moreover, Band structure and DOS analysis confirmed their semiconducting behavior, through direct band gaps ranging between 1.78eV to 2.21 eV and sulfur p-orbital contributions to conduction and valence states. MEP analysis highlighted heteroatom-rich regions as electrophilic/nucleophilic centers, supporting their potential to engage in favorable protein–ligand interactions. Hirshfeld surface analysis confirmed that crystal stability is primarily driven by π–π stacking, hydrogen bonding and Van der Waals forces, underlining the cooperative role of weak non-covalent interactions. Molecular docking with Human Metapneumovirus (HMPV) F fusion protein (PDB ID: 5WB0 ) and L polymerase (PDB IDs: 8FPI and 8FPJ ) demonstrated strong binding affinities (–8.0 to –9.8 kcal·mol⁻¹) and stable hydrogen bonding, π–π, and hydrophobic contacts with catalytically relevant residues. The convergence of quantum-chemical insights with docking outcomes underscores the promising role of oxazine derivatives as computationally investigated scaffolds for anti-HMPV drug design, warranting further in vitro and in vivo investigations.