Theoretical Investigation of the Electronic Structure and Reactivity of F-, Cl-, and Br- Substituted DL-Norvaline Derivatives: A DFT and Molecular Docking Study

This study theoretically investigates the influence of terminal halogen substitution on the electronic properties, reactivity, and biological interaction potential of DL-norvaline (Nva) and its derivatives (F-Nva, Cl-Nva, and Br-Nva). Density Functional Theory (DFT) calculations at the B3LYP/6-311G(d,p) level were employed to optimize molecular geometries and analyze electronic structures. Structural results indicate systematic bond elongation at the substitution site consistent with halogen atomic size. Frontier Molecular Orbital (FMO) and Density of States (DOS) analyses reveal that fluorine substitution slightly reduces the HOMO-LUMO gap (ΔE = 5.709 eV) relative to Nva (ΔE = 5.734 eV), suggesting enhanced chemical reactivity, whereas chlorine and bromine increase kinetic stability. Molecular Electrostatic Potential (MEP) mapping identifies the carboxyl and amine groups as dominant reactive centers, with fluorine inducing stronger charge polarization. Molecular docking against arginase (PDB: 5ZEF) shows favorable binding for all derivatives, with F-Nva exhibiting the highest affinity (-3.478 kcal/mol). These findings demonstrate that terminal halogenation effectively modulates electronic topology and bioactivity