Abstract: Curcumin, a naturally occurring polyphenol abundant in Curcuma species of the Zingiberaceae family, exhibits diverse pharmacological activities, including antioxidant and antitumor effects. In this study, density functional theory (DFT) was employed to comprehensively investigate the reactive sites of curcumin using multiple theoretical approaches, including frontier molecular orbital analysis, Mulliken charges, electrostatic potential (ESP) distribution, dipole moment, interaction region indicator (IRI), van der Waals potential, and bond order. This work not only provides a molecular- level theoretical foundation for understanding the chemical reactivity and pharmacological mechanisms of curcumin, which is crucial for elucidating its pharmacological mechanisms. The identified reactive sites offer valuable insights for the rational design of curcumin-based derivatives with improved solubility and targeted bioactivity. materials and methods: In this study, density functional theory (DFT) was employed to comprehensively investigate the reactive sites of curcumin using multiple theoretical approaches, including frontier molecular orbital analysis, Mulliken charges, electrostatic potential (ESP) distribution, dipole moment, interaction region indicator (IRI), van der Waals potential, and bond order. results: We successfully employed DFT to comprehensively analyze the molecular properties and reactive sites of curcumin. The results demonstrate that the curcumin molecule contains various functional groups (which form an extended conjugated system), adopts a non-planar conformation due to steric repulsion, and that the conjugation induces electron delocalization—an effect that significantly influences the molecule’s electronic properties and reactivity. Analyses of HOMO/LUMO, Mulliken atomic charges, and ESP distribution collectively identified oxygen atoms (particularly O1 and O5) as the primary sites for electrophilic attack, while positively charged carbon (e.g., C13) and hydrogen atoms (e.g., H41) were determined to be the main nucleophilic reaction sites. The presence of an intramolecular hydrogen bond, as revealed by the IRI, further enhances the electrophilic potential of O1. In the van der Waals potential profile of curcumin, repulsive potentials are predominantly distributed over the left benzene ring and the central carbon chain region, which helps prevent random molecular aggregation and ensures the exposure of active sites. Attractive potentials are localized in small regions such as O1, facilitating interactions with other molecules and promoting electrophilic reactions. discussion: This work not only provides a molecular-level theoretical foundation for understanding the chemical reactivity and pharmacological mechanisms of curcumin, but also offers valuable insights for the development of curcumin-based derivatives. conclusion: These findings provide theoretical insights into curcumin’s pharmacological mechanisms and guide future structural modifications to enhance its bioactivity.
Liu et al. (Fri,) studied this question.