<p>This study explores the electronic properties, reactivity, and biological potential of Vitamin B3 derivatives using computational approaches. Virtual modifications with various substituents were made to create a series of 20 candidates, based on chemical intuition and the impacts of electron-releasing and electron-donating atoms on chemical reactivity. Frontier molecular orbital analysis revealed that Vit B3-CH₂NHCHS exhibited the lowest energy gap (3.15&#xa0;eV), suggesting superior biological activity. Quantum chemical descriptors based on Koopmans’ theorem highlighted that CH₂NHCHS has the lowest hardness (1.58&#xa0;eV) and moderate global softness, indicating its stability and reactivity. Molecular docking studies with the KGPDC protein receptor showed strong binding affinities, with binding energies ranging from − 5.8 to − 6.1&#xa0;kcal/mol, comparable to known inhibitors. ADMET analysis confirmed favorable absorption properties, with molecules 1, 3, 4, and 6 showing BBB permeability and molecules 2 and 5 exhibiting high intestinal absorption. Molecular Electrostatic Potential (MEP) analysis identified nucleophilic attack sites in the hydroxyl group of the carboxyl moiety, while Hirshfeld surface analysis confirmed key hydrogen bonding interactions. Fukui function analysis predicted CCl₃ &gt; OCHF₂ &gt; OCF₃ &gt; CH₂CONH₂ &gt; CH₂NHCHS as the nucleophilic reactivity order, with Vitamin B3 being the most susceptible at 0.4938, while the electrophilic trend followed CH₂CONH₂ &gt; CH₂NHCHS &gt; OCF₃ &gt; CCl₃ &gt; OCHF₂, with Vitamin B3 being the most electrophilic at − 0.3240. These findings provide insights into the electronic structure, reactivity, and pharmacological potential of Vitamin B3 derivatives, supporting their application in drug discovery, particularly for antidiabetic, anti-inflammatory, and anticancer therapies. </p> Graphical Abstract <p></p>